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MELLON  LECTURE 

(UNDER  THE  AUSPICES  OF  THE  SOCIETY  FOR  BIOLOGICAL  RESEARCH) 
UNIVERSITY  OF  PITTSBURGH 


FIRST  LECTURE 


EXPERIMENTAL  AND  CHEMICAL  STUDIES 
OF  THE  BLOOD  WITH  AN  APPEAL  FOR 
MORE  EXTENDED  CHEMICAL  TRAIN- 
ING FOR  THE  BIOLOGICAL  AND 
MEDICAL  INVESTIGATOR 

BY 

JOHN  J.  ABEL 


1915 


EXCHANGE 


BIOLOGY 
LIBRARY 


EXPERIMENTAL  AND  CHEMICAL  STUDIES 
OF  THE  BLOOD  WITH  AN  APPEAL  FOR 
MORE  EXTENDED  CHEMICAL  TRAIN- 
ING FOR  THE  BIOLOGICAL  AND 
MEDICAL  INVESTIGATOR 


BY 

PROFESSOR  JOHN  J.  ABEL,  M.D.,  M.A.,  Sc.D. 

PROFESSOR  OF  PHARMACOLOGY  IN  THE  JOHNS 
HOPKINS  UNIVERSITY 


DELIVERED  ON  THE  OCCASION  OF  THE  OPENING  OF  THE 

MELLON  INSTITUTE  FOR  INDUSTRIAL  RESEARCH  ON 

THE  EVENING  OF  SATURDAY,  FEBRUARY  27,  1915 


MELLON  LECTURE 

(UNDER  THE  AUSPICES  OF  THE  SOCIETY  FOR  BIOLOGICAL  RESEARCH) 
UNIVERSITY  OF  PITTSBURGH 


FIRST  LECTURE 


EXPERIMENTAL  AND  CHEMICAL  STUDIES 
OF  THE  BLOOD  WITH  AN  APPEAL  FOR 
MORE  EXTENDED  CHEMICAL  TRAIN- 
ING FOR  THE  BIOLOGICAL  AND 
MEDICAL  INVESTIGATOR 


BY 

JOHN  J.  ABEL 


1915 


A3 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE 
BLOOD:  WITH  AN  APPEAL  FOR  MORE  EXTENDED 
CHEMICAL  TRAINING  FOR  THE  BIOLOGICAL  AND 
MEDICAL  INVESTIGATOR 

JOHN   J.   ABEL,     . 

Professor  of  Pharmacology  in  the  Johns  Hopkins  University 

Before  beginning  my  address  let  me  say  that  I  feel  it  to  be  a 
very  great  honor  to  have  been  asked  to  deliver  the  first  Mellon 
Lecture  under  the  auspices  of  the  Society  for  Biological  Research 
of  this  University.  The  establishment  of  a  lectureship  of  this 
character  is  a  great  encouragement  to  men  of  science.  It  affords 
additional  opportunity  to  bring  to  the  attention  of  a  wider  pub- 
lic the  recent  results  of  scientific  investigation  as  well  as  to 
emphasize  again  a  truth  which  can  not  be  too  often  repeated 
"that  science  constitutes  a  sure  and  lasting  part  of  the  intellec- 
tual treasure  which  mankind  possesses."1 

I  have  ventured  to  take  as  the  subject  of  my  address  some 
recent  experimental  and  chemical  studies  of  the  blood.  In 
order  to  give  my  subject  a  pfoper  setting  I  must,  first,  refer 
briefly -to  the  history  of  blood  letting,  and  to  make  clear  its 
relation  to  pressing  medical  problems,  I  shall  in  the  hour  discuss 
the  interaction  of  the  blood  and  the  organs  of  internal  secretion. 

The  overwhelming  significance  of  the  blood  to  all  people  in 
all  times  is  shown  in  folk  sayings,  in  tradition  and  in  literature. 
The  expressions,  "the  life  of  the  flesh  is  in  the  blood,"  "tainted 
blood,"  "blood  wiU  tell,"  "blood  oath,"  "blood  brother,"  all 
suggest  how  nearly  blood  has  been  held  to  be  synonymous  with 
life.  It  was  an  ancient  Celtic  custom  to  emphasize  the  inviola- 
bility of  a  treaty  by  having  it  written  with  the  blood  of  both 
clans  mixed  in  one  vessel. 

In  the  earlier  systems  of  medicine,  as  those  of  Asiatic  coun- 
tries, of  Egypt  and  of  Greece,  alterations  in  the  composition 

1  Ostwald. 


384741 


4  e    ,  i    ^JOHN   J.    ABEL 

of  the  blood  were  held  to  be  of  great  significance.  In  Hippocratic 
medicine  the- right  admixture  of  the  four  humors,  the  blood, 
phlegm,  yellow  bile  and  black  bile  constituted  health  while 
wrong  proportions  or  distribution  caused  disease.  This  humoral 
theory  of  disease,  variously  modified  down  to  our  own  time,  has 
always  fitted  in  well  with  the  practice  of  blood  letting,  or  making 
running  issues,  and  with  other  depletory  measures. 

Blood  letting  seems,  however,  to  antedate  all  systems  of  medi- 
cine and  to  have  been  one  of  the  earliest  therapeutic  procedures 
applied  by  primitive  races.  Leeches  have  been  used  for  this 
purpose  since  the  earliest  tunes  in  Asiatic  countries,  especially 
in  India,  and  let  no  one  suppose  that  their  use  has  been  discon- 
tinued in  our  day.  Dr.  Shipley,  the  master  of  Christ's  College, 
Cambridge,  writing  in  the  British  Medical  Journal2  tells  us  that 
the  Allies  and  Germans  are  now  fighting  on  some  of  the  best 
leech  areas  of  Europe  and  goes  on  to  state  that  the  traffic  in  leeches 
probably  reached  its  height  in  the  first  half  of  the  nineteenth 
century,  that  for  instance  in  the  year  1832,  57^500,000  of  these 
annelids  were  imported  into  France,  60,000  to  80,000  leeches  a 
day  frequently  leaving  Strassburg  for  Paris,  having  been  shipped 
overland  from  Hungary  via  Vienna.  So  great  was  the  demand 
that  the  artificial  cultivation  of  leeches  was  taken  up  in  various 
countries  and  became  a  profitable  industry.  And  now  a  new 
use  for  leeches  has  arisen.  Certain  glands  surrounding  the  oral 
end  of  the  digestive  canal  of  this  annelid  secrete  a  remarkable 
substance  which  keeps  blood  from  coagulating  and  which  has 
been  named  hirudin.  This  substance  is  much  used  in  our  labora- 
tories to  keep  the  blood  of  man  and  animals  in  the  fluid  state. 
Leeches  have  thus  become  an  article  of  commerce  quite  aside 
from  their  employment  as  depleting  agents  and  the  demand  is 
constantly  growing.  We  are  at  present  greatly  hampered  by 
our  inability  to  obtain  them  from  Europe,  as  their  importation 
has  practically  ceased  since  the  outbreak  of  the  war. 

2  No.  2813,  November  28,  1914,  p.  917,  and  No.  2814,  Decembers,  1914,  p.  962. 
These  papers  contain  much  valuable  information  concerning  the  medicinal 
leech  as  also  the  curious  history  of  exotic  leeches  which  in  certain  eastern  coun- 
tries constitute  a  serious  menace  to  the  life  of  men  and  animals. 


EXPERIMENTAL   AND    CHEMICAL   STUDIES   OF   THE   BLOOD         5 

It  is  not  my  purpose  to  attempt  to  give  a  history  of  blood 
letting,  even  in  abstract;  the  history  of  the  subject  is  practically 
co-extensive  with  the  history  of  medicine  itself.  I  must  therefore 
content  myself  with  a  few  selections  from  historical  writing  which 
will  demonstrate  to  you  that  the  influence  of  this  method  of  treat- 
ing disease  has  been  paramount  since  long  before  the  time  of 
Hippocrates  whose  writings  furnish  one  of  the  earliest  prescrip- 
tions for  blood  letting  beginning  with  the  direction  to  "Bleed 
in  the  acute  affections,  if  the  disease  appears  strong,  and  the 
patients  be  in  the  vigor  of  life,  and  if  they  have  strength." 

In  the  latter  part  of  the  twelfth  century,  when  universities 
as  we  now  know  them  were  coming  into  existence,  there  originated 
in  the  School  of  Salernum  the  Regimen  Sanitatis  Salerni,  or  Code 
of  Health,  a  poem  written  in  Latin  hexameter  verses  and  giving 
the  medical  notions  of  the  day,  as  derived  from  the  Arabic 
writers  in  regard  to  blood  letting,  diet  and  personal  hygiene. 
The  high  value  placed  on  the  Regimen  may  be  seen  from  the 
fact  that  it  passed  through  some  240  different  editions  and  was 
translated  into  all  the  known  languages.3  In  general  praise  of 
blood  letting  the  poem  says:4 

Bleeding  the  body  purges  in  disguise, 

For  it  excites  the  nerves,  improves  the  eyes 

And  mind,  and  gives  the  bowels  exercise, 

Brings  sleep,  clear  thoughts,  and  sadness  drives  away, 

And  hearing,  strength,  and  voice  augments  each  day. 

Other  verses  give  directions  as  to  what  months  are  proper 
and  what  improper  for  bleeding,  tell  what  diseases  are  benefited 
by  blood  letting  and  in  what  quantities  blood  should  be  drawn, 
and  the  effect  of  age  and  other  circumstances. 

Acute  disease,  or  only  so  in  part, 
Demands  blood  letting  freely  from  the  start, 
In  middle  age,  bleed  largely  without  fear 
But  treat  old  age  like  tender  childhood  here. 

3  Garrison:  The  history  of  blood  letting,  N.  Y.  Med.  Journ.,  March  1  and 8, 
1913. 

4  Professor  John  Ordronaux's  translation. 


6  JOHN   J.    ABEL 

In  the  latter  part  of  the  middle  ages  blood  letting  was  carried 
to  great  excess.  During  this  period  astrology  strongly  influ- 
enced medical  thought,  and  physicians  made  diagnoses  and  bled 
their  patients  according  to  the  position  of  the  planets,  constella- 
tions and  single  stars  (horoscopic  medicine).  For  their  greater 
convenience  semi-popular  calendars  were  even  prepared  with 
illustrations  such  as  the  so-called  venesection  manikins  of  Johann 
Nider  von  Gemlind  (1470)  and  of  Stoeffler  (1518)  with  direc- 
tions as  to  the  vein  to  be  opened  for  the  cure  of  each  malady. 
Figures  1  and  2  are  reproductions  of  old  plates  showing  some  of 
these  blood  letting  and  wound-men.5 

In  the  sixteenth  and  seventeenth  centuries  we  come  upon 
heated  controversies  between  the  upholders  of  the  Hippo- 
cratic  and  of  the  Arabian  theories  of  blood  letting.  By  the  former 
method  it  was  thought  that  the  vein  to  be  opened  should  be  as 
near  as  possible  to  the  diseased  part  in  order  that  the  "foul  and 
stagnant"  blood  might  be  directly  removed  from  the  inflamed 
area  ("Derivation").  On  the  other  hand,  the  doctrine  elabor- 
ated by  the  Arabians  taught  that  blood  should  be  taken  from  a 
vein  remote  from  the  inflamed  part,  for  instance,  in  inflamma- 
tion of  the  lungs  and  pleura,  from  the  arm  or  even  the  foot  of 
the  opposite  side  with  the  idea  that  this  process  ("Revulsion*') 
prevented  good  blood  from  accumulating  in  the  diseased  part. 

This  latter  doctrine  was  in  the  ascendancy  in  European  coun- 
tries in  the  sixteenth  century,  but  the  learned  Pierre  Brissot, 
(1478-1522)  basing  his  opinion  on  his  own  large  clinical  experi- 
ence in  Paris  in  1514  when  an  acute  affection  of  the  lungs  was 
prevalent,  revived  the  Hippocratic  method  of  bleeding  and 
thus  started  the  famous  Brissot-venesection  controversy  in  which 
most  of  the  great  men  of  the  century,  including  Vesalius,  took 
part.  The  importance  attached  to  the  controversy  at  the 
tune  is  shown  in  the  fact  that  the  opponents  of  Brissot  induced 
the  French  Parliament  to  forbid  the  practice  of  his  method,  and 
their  attacks  were  so  bitter  as  virtually  to  drive  him  from  Paris 

6  Figure  1  is  taken  f  rom  Heinrich  Stern' s  Theorie  und  Praxis  derBlutentziehung, 
Wurzburg,  1914.  Figure  2  from  Garrison:  The  history  of  blood  letting,  N.  Y. 
Med.  Journ.,  March  1  and  8,  1913. 


FIG.  1.    ADERLASS-MANNCHEN  AUS  STOEFFLER,  CALENDARIUM  ROMANUM 

MAGNUM.     OPPENHEIM  1518.     FOL.  14. 

The  numbers  indicate  the  points  at  which  veins  are  to  be  opened  for  this  or 
that  disease. 


FIG.  2.     SPECIMENS  OF  THE  Lasstafelkunst  (Horoscopic  Medicine  or  Judicial 

Astrology). 

B:  Blood-letting  man  (Aderlassmann),  from  the  Calendar  of  Regiomontanus 
(1475),  showing  the  points  of  election  for  blood-letting  under  the  signs  of  the 
Zodiac.  C:  Wound-man  (Wundenmanri) ,  from  Gersdorff's  Feldtbuch  (1517),  show- 
ing the  sites  for  ligation  of  the  different  arteries  or  for  blood-letting.  C  is  a 
later  evolutionary  form  of  the  old  zodiacal  diagrams,  which  combined  an  expo- 
sition of  planetary  influences  with  schemata  of  the  viscera  (B). 


EXPERIMENTAL   AND    CHEMICAL   STUDIES    OF   THE    BLOOD         7 

and  his  professorship.  Haeser6  informs  us  that  the  quarrel 
assumed  such  violence  that  when  the  University  of  Salamanca 
took  sides  with  Brissot,  the  Emperor  Charles  V  who  was  called 
on  to  render  a  "decision"  in  the  matter  was  assured  that  the  new 
false  doctrine  was  no  less  dangerous  than  the  heresy  of  Luther. 
While  Brissot  was  anything  but  a  "therapeutic  nihilist" 
as  to  bleeding  and  held  firmly  to  the  doctrine  that  the  "foul 
blood"  of  the  inflamed  area  should  be  removed,  some  of  his  fol- 
lowers rejected  bleeding  altogether  in  acute  disease  of  the  lungs 
and  pleura  (the  pleuritis  of  that  day).  Their  moderation  was 
looked  upon  as  little  less  than  heretical  and  toward  the  end 
of  the  sixteenth  century  we  find  Leonardo  Botallo,  a  Piedmon- 
tese,  an  eminent  practitioner  of  his  time,  chief  physician  to  Charles 
IX,  advising  venesection  to  the  limit  regardless  of  the  nature  of 
the  disease,  the  age  or  condition  of  the  patient.  Blood  lettings 
of  3-4  pounds  each  repeated  as  often  as  four  or  five  tirnes  were 
advised,  says  Haeser,  and  this  historian  adds  that  the  explana- 
tion of  this  "Vampyrismus"  is  probably  to  be  found  in  the 
circumstance  that  Botallo  lived  in  northern  Italy  where  diseases 
of  an  inflammatory  character  were  prevalent  and  more  especially 
that  in  his  experience  as  an  army  surgeon  he  encountered  only 
patients  of  the  most  robust  type.  Botallo,  in  defending  his 
practice  said,  "the  more  foul  water  is  drawn  from  a  well,  the 
more  good  water  can  flow  in  to  replace  it."7  An  ardent  follower 
of  Botallo  was  Riolan  the  younger  who  falls  back  upon  Hippoc- 
rates and  Galen  and  lays  down  the  rule  that  one  must  take  away 
as  much  blood  as  possible  in  every  disease.  As  an  adult  is 
judged  to  have  about  30  pounds  of  blood8  (!)  the  tapping  of  half 
this  amount,  or  15  pounds,  in  the  course  of  14  days  would  be 
about  the  right  amount  to  take,  says  Riolan.  Guy  Patin  (1602- 
1672),  himself  an  ardent  bleeder  and  purger,  informs  us  that 
Bovard,  body  physician  of  Louis  XIII,  bled  that  monarch  47 
times,  gave  him  312  clysters  and  prescribed  emetics  and  purges, 
215  times  all  in  one  year. 

6  Geschichte  der  Medicin,  vol.  2,  p.  64. 

7  Bauer:    Geschichte    der    Aderlasse,    Gekronte    Preisschirft,    Munich,  1870. 

8  Bauer:  loc.  cit.,  p.  139. 


8  JOHN   J.    ABEL 

A  little  later,  that  able  and  credulous  Belgian  mystic  and 
follower  of  Paracelsus,  J.  B.  Van  Helmont  (1578-1644),  an  icono- 
clast in  general,  called  by  his  admirer,  Haeser,  "the  fist  of  the 
seventeenth  century,"  went  so  far  as  to  condemn  venesection 
entirely.  To  him  is  attributed  the  often  quoted  phrase  "a  bloody 
Moloch  presides  in  the  chair  of  medicine." 

Also  as  holding  that  in  place  of  excessive  blood  letting  should 
be  substituted  therapeutic  procedures  ("Alterantia")  and  change 
of  diet,  stands  the  genial  and  talented  Franciscus  de  le  Boe  (Syl- 
vius) (1614-1672),  one  of  the  leading  medical  authorities  of  the 
seventeenth  century  and  one  of  the  earliest  defenders  of  Har- 
vey 's  doctrine  of  the  circulation,  who  taught  at  Ley  den  that 
abnormal  fermentations  in  the  fluids  of  the  body  cause  disease— 
a  variant  of  the  ancient  humoral  doctrine.  In  Chapter  XX  of 
his  "New  Idea,"  (translated  by  Richard  Gower,  London,  1675) 
entitled  "On  the  Motion  of  Blood  through  the  Lungs  Affected," 
he  shows  his  good  sense  and  his  caution,  when  he  says: 

A  Plethora  of  Blood  is  soon  and  safely  Cur 'd, by  a  sufficient  Empty- 
ing of  it  by  opening  a  Vein;  whether  it  be  together  and  at  once,  or  by 
repeted  turns,  according  to  the  peculiar  nature  and  strength  of  the 
Sick.  For  there  are  many  who  cannot  bear  to  have  much  taken  away 
together,  but  soon  fall  into  a  Swouning;  by  which  seeing  none  can  at 
any  time  receive  any  good,  I  had  rather  th^t  it  should  be  prevented, 
as  often  as  may  be,  and  every  Cure  be  done  securely  rather  than  rashly, 
seeing  it  often  happens  to  those  rash  Blood  Letters,  that  they  educe 
Life  together  with  Blood." 

An  instance  of  lavish  blood  letting  in  a  medical  crisis  may  be 
found  in  the  experience  of  that  adventurous  spirit,  Thomas 
Dover,  to  whom  we  owe  the  much  used  "Dover's  powder." 
In  1708,  Dover,  then  48  years  old,  set  out  on  a  privateering 
expedition  and  was  given  command  of  a  ship,  the  Duke,  while 
his  superior,  Captain  Woodes-Rogers,  took  command  of  the 
other  ship  of  the  squadron,  the  Duchess.  The  three  years' 
voyage  of  these  buccaneers  is  of  interest  historically  because 
"touching  at  the  island  of  Juan  Fernandez,  they  took  on  board 
Alexander  Selkirk  who  had  lived  alone  on  the  island  for  four 


EXPERIMENTAL    AND    CHEMICAL    STUDIES    OF    THE    BLOOD         9 

years  and  four  months,  and  whose  story  was  to  develop  in  the 
skilful  hands  of  Defoe  into  that  of  the  immortal  "Robinson 
Crusoe."9  In  Dover's  "Ancient  Physician's  Legacy  to  his 
Country/'  we  find  the  following  interesting  passages: 

When  I  took  by  Storm  the  two  Cities  of  Guaiaquil,  under  the  Line, 
in  the  South  Seas,  it  happened,  that  not  long  before,  the  Plague  had 
raged  amongst  them.  For  our  better  Security,  therefore,  and  keep- 
ing our  People  together,  we  lay  in  their  Churches,  and  likewise  brought 
thither  the  Plunder  of  the  Cities:,  ...  In  a  very  few  days  after 
we  got  on  board,  one  of  the  Surgeons  came  to  me,  to  acquaint  me,  that 
several  of  my  Men  were  taken  after  a  violent  Manner,  with  that  Langour 
of  Spirits,  that  they  were  not  able  to  move.  I  immediately  went  among 
them,  and,  to  my  great  Surprise,  soon  discerned  what  was  the  Matter. 
In  less  than  Forty-eight  Hours  we  had  in  our  several  Ships,  one  Hun- 
dred and  eighty  Men  in  this  miserable  condition. 

I  ORDER'D  the  Surgeons  to  bleed  them  in  both  Arms,  and  to  go 
round  to  them  all,  with  Command  to  leave  them  bleeding  till  all  were 
blooded,  and  then  come  and  tie  them  up  in  their  Turns.  Thus  they 
lay  bleeding  and  fainting,  so  long,  that  I  could  not  conceive  they  lost 
less  than  an  hundred  Ounces  each  Man. 

If  we  had  lost  so  great  a  Number  of  our  People,  the  poor  Remains 
must  infallibly  have  perished.  .  .  .  We  had  on  board  Oil  and 
Spirit  of  Vitriol  sufficient,  which  I  caused  to  be  mixed  with  Water  to 
the  Acidity  of  a  Lemon,  and  made  them  drink  very  freely  of  it;  so  that 
notwithstanding  we  had  one  hundred  and  eighty  odd  down  in  this 
most  fatal  Distemper,  yet  we  lost  no  more  than  seven  or  eight;  and 
even  these  owed  their  Deaths  to  the  strong  Liquors  which  their  Mess- 
Mates  procured  for  them.  .  .  Now  if  we  had  had  Recourse  to  Alexi- 
pharmicks,  such  as  Venice  Treacle,  Diascordium,  Mithridate,  and 
such-like  good-for-nothing  Compositions,  or  the  most  celebrated 
Gascoin's  Powder,  or  Bezoar,  I  make  no  Question  at  all,  considering 
the  heat  of  the  Climate,  but  we  had  lost  every  Man. 

Of  non-medical  literature  the  satire  of  Gil  Bias,  written  early 
in  the  eighteenth  century  but  in  reality  giving  a  picture  of 
seventeenth  century  excesses  in  blood  letting,  is  worth  citing. 

Dr.  Sangrado  is  called  in  to  prescribe  for  a  gouty  old  canon, 
and  he  at  once  sends  for  a  surgeon  and  orders  him  to  "take  6 

9  Chronicles  of  Pharmacy,  Wootton,  ii,  p.  130. 


10  JOHN   J.    ABEL 

good  porringers  of  blood  in  order  to  supply  the  need  of  perspira- 
tion." The  surgeon  was  ordered  to  return  in  three  hours  and 
take  as  much  more  and  to  repeat  the  evacuation  the  next  day. 
The  patient  was  "reduced  to  death's  door  in  less  than  two  days, 
and  the  notary  being  summoned  to  make  the  will  seized  his 
hat  and  cloak  in  a  hurry  when  he  learned  from  the  messenger 
Gil  Bias,  that  Dr.  Sangrado  was  the  physician.  "Zooks," 
cried  he,  "let  us  make  haste,  for  the  doctor  is  so  expeditious 
that  he  seldom  gives  the  patient  time  to  send  for  notaries ;  that 
man  has  choused  me  out  of  a  great  many  jobs." 

But  the  misuse  of  bleeding  continued  in  the  centuries  fol- 
lowing and  at  no  time  was  the  practice  more  abused  than  in  the 
latter  part  of  the  eighteenth  or  even  in  the  first  five  decades  of 
the  past  century.  French  and  Italian  authorities  especially, 
were  great  believers  in  blood  letting.  Broussais  (1772-1832) 
is  said  to  have  used  100,000  leeches  in  his  hospital  wards  in 
one  year.  This  physician  and  his  follower,  Bouilland,  actuated 
by  false  theories  of  the  cause  of  fevers,  recommended  the  bleed- 
ing of  a  patient'  10  to  12  and  even  20  times  in  the  course  of 
treatment. 

But  more  and  more  the  opponents  of  general  and  excessive 
bleeding  made  headway  in  their  respective  countries.  Many 
are  the  names  that  might  here  be  named,  as  Pinel,  Andral, 
Louis  in  France,  Dietl,  the  pupil  of  Skoda,  and  Wollstein  the 
professor  of  veterinary  medicine  in  Vienna,  Mezler,  Rademacher, 
von  Pfeufer  and  others  in  Germany,  Marshall  Hall10  and  later 
Sir  William  Jenner,  Sir  William  Gull,  Bennet  and  others  in 
England,  Strambio,  Angeli,  Meli  in  Italy,  and  Jackson  in  our 
own  country,  and  many  others  in  all  of  these  countries. 

But  what  finally  led  to  the  entire  abolition  of  bleeding  after 
the  middle  of  the  past  century  was  not  so  much  the  opposition 
of  clinicians  who  failed  by  its  use  to  abort  pneumonia,  ("the 
queen  of  inflammations,"  as  Dietl  calls  it),  or  some  other  acute 

10  < <\yhile  Marshall  Hall  favored  venesection  he  was  one  of  the  earlier  and 
important  members  of  the  profession  to  throw  doubt  upon  indiscriminate  blood 
letting."  D'Arcy  Power:  Dr.  Marshall  Hall  and  the  decay  of  blood  letting, 
The  Practitioner,  1909,  vol.  32,  p.  320. 


EXPERIMENTAL   AND    CHEMICAL    STUDIES    OF   THE    BLOOD       11 

disease,  but  the  rise  of  new  theories  of  disease,  based  on  discoveries 
of  fundamental  importance.  The  rise  of  the  cell-theory  and  of 
cellular  pathology,  the  discovery  of  bacteria  and  their  con- 
nection with  the  inflammatory  processes  of  the  infectious  diseases, 
the  appearance  of  hydrotherapy,  the  expectant  medicine  of  the 
school  of  Skoda  and  Oppolzer,  new  and  quicker  methods  of  ob- 
taining the  effects  of  drugs  as  by  means  of  the  hypodermic 
syringe,  the  discovery  of  new  hypnotics,  of  the  analgesics  and 
anaesthetics,  altered  the  views  of  medical  theorists  and  practi- 
tioners alike  and  inevitably  led  to  the  downfall  of  the  theories 
on  which  venesection  has  been  based. 

During  a  period  of  study  of  six  and  a  half  years,  (1884-1891) 
as  a  student  of  chemistry  and  medicine  in  several  of  the 
larger  medical  centers  in  Germany,  Austria  and  Switzerland, 
I  never  once  saw  a  patient  bled  in  clinic  or  hospital.  The  pro- 
cedure may  have  been  employed  now  and  then — but  so  little 
stress  was  laid  upon  it  that  it  was  not  thought  worth  while  to 
demonstrate  it  to  the  young  men  who  walked  the  wards.11 

Bleeding  did  not  disappear,  however,  from  the  world.  The 
common  man,  especially  in  Germany  and  France,  still  held 
firmly  that  benefits  did  follow  the  use  of  the  wet  cup,  the  lancet 
and  the  leech.  Tenaciously  the  old  practices  were  upheld.  If 
physicians  refused  to  bleed,  there  was  always  the  barber  sur- 
geon, fully  competent,  as  in  teeth  pulling,  to  give  relief.  I 
remember  that  in  my  boyhood  in  Ohio  the  practice  of  blood  let- 
ting in  the  spring  of  the  year  was  in  vogue  among  the  farm 
laborers  from  southern  Germany.  After  their  return  from  a 
visit  to  the  barber  surgeon  in  the  town  the  scarified  backs  were 
exhibited  as  a  special  favor,  and  irrefutable  arguments  advanced 

11  See  also  F.  de  Havilland  Hall:  The  Westminster  Hospital  Reports,  Vol. 
xvii,  p.  1,  1911,  who  makes  the  following  statement  in  a  clinical  lecture  on  blood 
letting:  "To  such  an  extent  had  bleeding  been  discarded  that  during  my  student 
days  at  St.  Bartholomew's  Hospital,  I  never  heard  of  a  patient  being  bled,  so 
that  I  was  quite  taken  back,  when,  shortly  after  I  was  appointed  house  surgeon 
at  a  country  hospital,  the  senior  surgeon  came  to  me  to  be  bled.  Indeed  in  1892 
when  I  requested  a  member  of  the  surgical  staff  at  St.  Bartholomew's  to  bleed  a 
patient  for  me,  he  told  me  that  this  was  the  first  time  he  had  ever  been  called  upon 
to  perform  phlebotomy." 


12  JOHN   J.    ABEL 

in  respect  to  the  benefits  of  bleeding  either  to  ward  off  disease  or 
to  improve  nutrition.  Was  it  not  true  and  known  to  all  stock 
breeders  that  the  domestic  animals  could  be  fattened  by  judi- 
cious bleeding  at  certain  fixed  intervals? 

And  it  appears  now  that  the  common  man  was  right  after  all. 
An  empirical  method  of  treatment  which  has  been  practiced 
by  nearly  all  races  since  before  the  day  of  Hippocrates  almost 
certainly  contains  a  basis  of  truth.  This  is  now  admitted,  and 
physicians  are  again  saving  lives  by  the  judicious  and  timely 
use  of  blood  letting.  Says  the  experienced  Sir  T.  Lauder  Brun- 
ton:  "Blood  letting  not  only  relieves  symptoms  but  may  save 
the  patient's  life,  as  in  engorged  conditions  of  the  right  heart, 
whether  due  to  mitral  incompetence  or  pulmonary  affections."12 
In  puerperal  eclampsia,  to  mention  but  one  more  instance,  we 
also  have  a  condition  which  is  generally  strikingly  benefited  by 
blood  letting.13 

Venesection,  then,  will  probably  never  again  be  entirely  ex- 
cluded from  medicine,  as  it  was  during  the  last  quarter  of  the 
past  century,  nor  need  we  fear  that  the  practice  will  be  again 
misused. 

I.    PLASMAPHAERESIS 

But  venesection,  like  all  therapeutic  procedures,  has  cer- 
tain drawbacks  which  prescribe  limits  to  its  use  and  these  draw- 
backs are  inherent  in  the  very  composition  of  the  blood  and  in 
the  nature  of  the  circulatory  apparatus.  As  is  known  to  all 
the  oxygen-carrying  power  of  the  blood  resides  in  the  red  cor- 
puscles, or  erythrocytes,  which  constitute  about  36  per  cent  of 
the  volume  of  the  blood.  These  erythrocytes,  like  other  cellular 
constituents,  can  be  built  up  only  slowly  in  the  body  by  the 

12  On  the  use  of  leeches  in  relieving  overdistension  of  the  right  heart,  in  cases 
of  pneumonia  see  D.  B.  Lees,  Lancet,  February  25,  1911.    Also  for  cases  in  which 
blood  letting  (either  by  venesection  or  by  means  of  leeches),  may  be  advan- 
tageously employed,  see  F.  de  Havilland  Hall;  Westminster  Hospital  Reports, 
vol.  17,  p.  1,  1911. 

13  See  Zweifel:  Zur  Behandlung  der  Eklampsie,  Centrabl,   f.  Gynakologie, 
1895,  No.  46.    Alexander  Strubell:  Der  Aderlass,  eine  monographische  Studie, 
Berlin,  1905. 


EXPERIMENTAL   AND    CHEMICAL   STUDIES   OF   THE   BLOOD       13 

haemapoietic,  or  blood  building,  organs.  It  is  apparent,  there- 
fore, that  the  bad  effects  of  overbleeding,  as  formerly  practiced, 
might  be  due  mainly  to  the  loss  of  these  cellular  elements.  Com- 
mon experience  has  shown  that  the  loss  of  too  much  blood  is 
either  immediately  fatal,  or  else  is  followed  by  a  prolonged  ill- 
ness, recovery  from  which  is  often  doubtful. 

Reflecting  on  these  drawbacks  I  conceived  the  idea  that  the 
main  objection  of  blood  letting  could  be  obviated  by  the  speedy 
return  into  the  body  of  the  red  and  the  white  corpuscles  instead 
of  throwing  them  away  as  hitherto  has  been  our  custom.  The 
only  thing  that  would  be  removed  from  the  blood  of  a  person 
bled  in  this  way  would  be  its  fluid  part — the  plasma.  If  this 
method  were  found  to  be  practicable  the  value  of  bleeding  would 
be  enhanced  and  its  field  of  application  extended.  Such  a 
method,  if  successful,  would  appear  to  be  advantageous  for  the 
patients,  not  only  in  those  instances  in  which  venesection  is 
performed,  admittedly  with  good  results,  but  would  also  open 
the  way  for  the  withdrawal  of  fluid  when  it  is  desired  to  decrease 
the  volume  of  blood  in  the  vascular  apparatus  or  to  remove  ex- 
cess of  deleterious  substances,  or  where  bleeding  has  hitherto 
been  contraindicated  because  of  the  danger  of  reducing  the 
oxygen-carrying  capacity  of  the  blood,  as,  for  example,  in  aneur- 
ism, or  in  cardiac  decompensation  with  a  low  blood  count. 

In  the  work  now  going  on  in  my  laboratory,  we  are  still  in  the 
stage  of  experimentation  and  study,  but  our  experiments  on  ani- 
mals have  proved  the  feasibility  of  the  method.  With  the 
skillful  cooperation  of  my  colleagues,  Drs.  Rowntree,  Turner, 
Marshall  and  Lamson,  a  considerable  number  of  experiments 
on  animals  have  already  been  made.  Our  procedure,  in  a  word, 
is  the  following.  Blood  is  withdrawn  freely  from  an  animal  and 
is  prevented  from  clotting  by  addition  of  leech  extract;  Locke's 
fluid  in  equal  volume  is  then  added  to  the  blood,  and  the  mixture 
is  sedimented  in  the  centrifugal  machine  until  the  corpuscles 
have  settled  out  in  the  flasks.  The  supernatant  plasma  is  then 
drawn  off  and  replaced  by  Locke's  fluid,  the  corpuscles  are 
stirred  up  and  the  new  mixture  is  returned  to  the  animal.  By 
repeating  this  process  it  has  been  learned  that  blood  letting  can 


14  JOHN   J.    ABEL 

be  carried  out  repeatedly,  without  endangering  the  life  of  an 
animal  provided  only  that  the  cellular  elements  of  the  blood 
are  returned.  We  have  named  the  procedure  plasmaphaeresis. 

It  is  apparent  that  when  blood  letting  is  practiced  in  the 
usual  way  there  is  always  the  risk  of  greatly  reducing  the  oxy- 
gen-carrying capacity  of  the  blood  through  loss  of  red  corpuscles, 
but  in  our  experiments  the  fluid  of  the  blood  can  be  withdrawn 
in  large  quantities  without  affecting  this  capacity,  as  far  as  we 
can  determine  at  the  present  moment.  Just  how  large  quan- 
tities of  plasma  can  be  withdrawn  without  permanent  injury 
cannot  at  present  be  stated.  In  certain  cases  very  large  amounts 
have  been  successfully  removed  in  experiments  extending  over 
several  days.  We  have  actually  withdrawn  from  a  dog  by 
repeated  bleedings  in  a  single  day,  a  volume  of  blood  more  than 
twice  that  contained  in  the  body,  with  no  apparent  injury, 
by  our  method  of  returning  the  corpuscles  after  each  bleeding. 
How  far  this  exceeds  the  quantity  of  blood  that  may  be  safely 
removed  from  a  dog  at  one  time  without  return  of  corpuscles 
is  seen  when  we  recall  that  the  loss  at  one  time  of  60  to  70  per 
cent  of  the  animal's  blood  is  quickly  fatal. 

It  may  yet  be  possible  to  attach  an  electrically  controlled 
centrif ugalizing  apparatus  directly  to  the  blood  vessels  of  an 
animal  and  tap  off  a  desired  quantity  of  the  fluid  part  of  the 
blood  while  directing  the  stream  of  corpuscles  back  into  the 
body  (or  vice  versa),  the  whole  apparatus  being  analogous  in 
a  way  to  the  modern  cream  separator. 

It  has  been  our  purpose  in  our  recent  experiments  to  find 
the  limits  to  which  plasmaphaeresis  may  be  carried  and 
to  learn  what  pathological  changes  ensue  when  the  procedure 
is  carried  to  a  point  beyond  which  life  is  endangered.  With 
the  form  of  Locke's  solution  now  employed  by  us,  we  have,  in 
the  course  of  five  days,  carried  the  removal  of  plasma  to  a  point 
where  the  total  volume  of  blood  withdrawn  from  the  body  equals 
at  least  five  times  that  ordinarily  contained  in  the  body.  In 
this  experiment  the  limit  of  the  procedure  was  probably  reached, 
as  the  animal  was  very  nearly  lost  during  the  last  bleeding; 
only  the  speedy  return  of  the  sedimented  corpuscles  saved  the 


EXPERIMENTAL   AND    CHEMICAL    STUDIES    OF   THE    BLOOD       15 

dying  animal.  Unfortunately  one  cannot  conclude  from  these 
most  successful  experiments  that  similar  or  even  markedly  lower 
quantities  can  always  be  removed  without  danger.  We  have 
recently  carried  out  a  large  number  of  experiments  with  a  view 
to  determine  the  safe  limits  of  plasmaphaeresis  both  as  to  quan- 
tity per  day  and  total  quantity  of  blood  withdrawn,  but  un- 
fortunately these  experiments  are  vitiated  by  an  error  which 
has  only  recently  been  discovered.  It  has  been  found  that 
the  imported  hirudin  which  we  are  now  using  is  strongly  toxic. 
This  was  not  the  case  with  the  product  which  we  ourselves 
manufactured  and  which  was  used  in  our  earlier  experiments. 
Further  experiments  will  have  to  be  done,  therefore,  to  settle 
this  question. 

Some  interesting  results  have  been  obtained  by  studying 
the  chemical  changes  during  plasmaphaeresis.  Since  the  method 
consists  essentially  in  replacing  the  plasma  of  the  blood  by  a 
saline  solution,  it  is  natural  to  find  a  decrease  in  the  soluble 
proteins  of  the  blood.  While  not  as  rapid  as  a  purely  mathemati- 
cal calculation  based  on  the  amounts  drawn  off  and  returned 
would  indicate,  if  the  vascular  system  were  regarded  as  a  vessel 
of  given  capacity  to  be  washed  out,  the  decrease  is  considerable. 
In  three  days  the  soluble  proteins  have  been  reduced  ,to  about 
one-third  their  original  value,  after  which  there  is  a  slight  rise 
as  the  process  is  continued.  Evidently,  as  was  expected,  there 
is  a  continual  renewal  of  plasma  proteins  from  the  tissues. 

In  striking  contrast  to  this,  the  non-pro teid  nitrogen  of  the 
plasma  shows  a  slight  rise  on  the  first  day  in  every  case  studied, 
and  a  tendency  to  rise,  with  some  fluctuations,  as  the  process 
is  continued.  This  increase,  which  is  chiefly  due  to  urea,  may 
be  due  either  to  an  increase  in  nitrogenous  catabolism  or  to  a 
diminution  of  nitrogen  excretion. 

Studies  have  also  been  made  of  blood  pressure  and  blood 
counts.  Plasmaphaeresis,  like  haemorrhage,  causes  seemingly 
a  paradoxical  increase  in  the  number  of  red  cells  per  unit  volume 
of  blood.  This,  which. appears  to  be  a  general  phaenomenon 
accompanying  temporary  asphyxia,  is  being  investigated  in  all 
its  bearings  by  Dr.  Lamson  (Polycythaemia,  P.  D.  Lamson; 


16 


JOHN   J.    ABEL 


Jour.  Pharm.  and  Expt.  Ther.  vii,  No.  1,  July,  1915).  The 
blood  pressure,  which  falls  on  bleeding,  is  restored  to  a  satis- 
factory value  on  returning  the  corpuscles  and  for  a  long  period 
the  two  changes  may  nearly  compensate  each  other.  A  slight 
downward  tendency  is  noticed,  however,  as  plasmaphaeresis 
is  continued  and  in  the  end  a  dangerously  low  point  (about  50 
mm.)  will  be  reached  on  withdrawing  amounts  of  blood  consider- 
ably smaller  than  those  taken  at  the  start.  The  previous 
bleeding  usually  shows  a  fall  to  a  point  (from  60  to  80  mm.) 
which  should  be  regarded  as  a  warning,  even  though  100  mm. 
or  more  may  be  reached  on  reinjection. 

The  following  tables  give  in  condensed  form  some  of  the 
data  to  which  reference  has  been  made  in  the  foregoing  pages. 

The  results  obtained  in  continued  plasmaphaeresis  are  shown 
in  table  3.  The  amount  of  blood  taken  was  about  one  volume 
on  each  day.  The  first  two  columns  of  analytical  results,  ob- 
tained with  samples  taken  at  the  beginning  and  end  of  the 

TABLE  i 

Plasmaphaeresis  on  three  dogs  for  several  days.    Nos.  8  and  11  three  days  each, 

No.  10  two  days 


EXPERIMENT   NO. 

8 

10 

11 

Weight  before  operation  
(Estimated)  blood  volume  
Total  blood  drawn  
Ratio  of  volumes 

9.6  kg. 
730  cc. 
2037  cc. 
279 

12.8  kg. 
960  cc. 
2046  cc. 
2.13 

8kg. 
600  cc. 
1835  cc. 
3.06 

Weights,  July  8  
Weights,  July  10 

10.5  kg. 
10.7  kg. 

11.8  kg. 
12.5  kg. 

8.5  kg. 
8.0  kg. 

Weights,  July  15  

11.2  kg. 

12.8  kg. 

8.2  kg. 

Blood  count  (millions)  July  8.  .  .  . 
Blood  count  (millions)  July  9.  .  .  . 
Blood  count  (millions)  July  13.  .. 
Blood  count  (millions)  July  16.  .. 
Haemoglobin,  July  8  
Haemoglobin,  July  9 

4.5 
4.6 
4.2 
5.2 
52  per  cent 
52  per  cent 

5.3 
5.9 
5.5 
6.2 
74  per  cent 
65  per  cent 

6.5 
5.1 

5.8 

78  per  cent 

Haemoglobin,  July  13  
Haemoglobin,  July  16  
Weights,  July  22  
Blood  count,  July  22  
Haemoglobin,  July  22 

60  per  cent 
65  per  cent 
11.0kg. 
4.1 
72  per  cent 

80  per  cent 
79  per  cent 
1  13.35  kg. 
5.4 
80  per  cent 

79  per  cent 
80  per  cent 
8.5  kg. 
5.3 
75  per  cent 

EXPERIMENTAL  AND    CHEMICAL   STUDIES   OF   THE   BLOOD       17 


TABLE  2 

Chemical  analysis 
Plasmaphaeresis  for  one  day,  on  three 


DATE 

DEC.  21 

JAN    11 

J\N    18 

Weight  of  dog 

15  1  kg 

11  9  kg 

7  1  ke 

Blood  volume  estimated  at  7.5 
per  cent 

1132  cc. 

892  cc. 

532  cc 

Total  volume  bled  and  per  cent 
of  total  blood  
Number  of  bleedings  

Results  of  Analyses 
Percentages 

Total  protein  of  blood  
Protein  of  plasma 

1185cc.  =  105% 
3 

Before        After 
Plasmaphaeresis 

22.27    25.23 
6  62      3  63 

1150  cc.  =  129% 
3 

Before        After 
Plasmaphaeresis 

25.15    25.32 
6  59      3  17 

410cc.=77% 
5 

Before        After 
Plasmaphaeresis 

17.34    17.19 
6  28      3  68 

Difference  of  above*  
Blood  counts,  millions  .            .  . 

15.65    21.60 
9  0      11.7 

18.56    22.15 
11  8      12.9 

11.06    13.51 
6.6        7.5 

Total  non-proteid  N  
Urea  nitrogen  
Non-urea  nitrogen 

0.037    0.039 
0.016    0.019 
0  021     0  020 

0.029    0.036 
0.011    0.017 
0  018    0  021 

0.045    0.055 
0.016    0.023 
0  029    0  032 

Amino  nitrogen  

0.0041 

0.0048  0.0048 

*Blood  taken  for  analysis  not  included  unless  made  up  by  equal  amount  of 
washed  corpuscles  from  other  dogs. 

TABLE  3 
Continued  plasmaphaeresis  on  a  dog  for  five  successive  days 

Experiment  No.  6,  January  22  to  26,  1915,  inclusive.    A, before  plasmaphaere- 
sis; B,  after  plasmaphaeresis. 

Weight  of  dog  8.5  kg.     Estimated  blood  volume  (7.5  per  cent)   =   (640  cc.). 
Total  blood  removed  in  five  days  3335  cc.  =  521  per  cent. 

Analytical  results  in  percentage  of  total  blood 


DATE  

A,  JAN.  22 

B,  JAN.  22 

B,  JAN.  24 

B,  JAN.  26 

FEB.   19 

Total  protein  of  blood  
Plasma  protein  
Difference  of  above  

19.28 
6.38 
12.90 

19.31 
3.44 

15.87 

16.81 
2.23 
14.58 

15.83 
2.92 
12.91 

11.78 
5.75 
6.03 

Blood  count  millions 

8  5 

8.5 

7.5 

6.5 

3.5 

Total  non-proteid  nitrogen... 
Urea  nitrogen  
Amino  nitrogen 

0.035 
0.013 
0  0047 

0.040 
0.019 
0  0056 

0.037 
0.014 
0.0033 

0.042 
0.021 
0.0059 

0.030 
0.012 
0.0038 

day's  work,  compare  closely  with  those  in  table  1.     The  third 
column  shows  the  results  at  the  end  of  the  third  day's  work, 


18 


JOHN   J.    ABEL 


when  the  plasma  protein  reached  the  lowest  value,  2.23  per 
cent.  The  fourth  column  gives  the  results  at  the  end  of  five 
days  of  plasmaphaeresis  while  the  last  column  shows  the  results 
24  days  later.  Here  the  plasma  protein  has  gone  up  again  nearly 
to  its  original  value.  The  corpuscles  protein,  and  consequently 
the  total  protein,  also,  are  low  owing  to  the  anaemia. 

Influence  of  plasmaphaeresis  on  blood  pressure 

Mean  systolic  pressures  in  millimeters  of  mercury 

Experiment  No.  6,  January  22  to  26,  1915,  inclusive 


BLEEDING 

RETURN  OF  CORPUSCLES 

DAY  OF  EXPT. 

VOLUME  BLED 

Before 

After 

Before 

After 

CC. 

1st      .  . 

250 

208 

165 

202 

250 

115 

65 

95 

•135 

170 

140 

65 

85 

115 

2nd  

200 

125 

pressures  not  observed  on  this  day 

170 

3rd 

195 

130 

110 

210 

130 

60 

110 

200 

110 

55 

70 

110 

185 

135 

50 

105 

4th 

205 

135 

100 

110 

135 

200 

135 

105 

100 

120 

200 

115 

60 

80 

105 

135 

95 

50 

75 

105 

5th  

180 

105 

100 

110 

190 

120 

52 

65 

105 

175 

100 

50 

47. 

95 

1  hr.  later  =   110 

II.    VIVIDIFFUSION 

I  should  like  now  to  describe  a  second  method  for  the  study 
of  the  blood,  and  to  state  briefly  some  of  the  results  that  have 
already  been  obtained  by  its  use.  But  first  let  me  remind  you 
that  there  are  numerous  constituents  of  the  blood  derived  from 
various  organs  which  are  of  the  most  vital  significance  to  the 


FIG.  3.     PERSPECTIVE  VIEW  OF  VIVIDIFFUSION  APPARATUS;  EARLIER  FORM  WITH 

SIXTEEN  TUBES 

A,  arterial  cannula;  B,  venous  cannula;  C,  side  tube  for  introduction  of 
hirudin;  D,  inflow  tube;  E,  outlet  tube;  F,  G,  supporting  rod  attached  at  H 
and  K  to  branched  U-tubes;  L,  burette  for  h'rudin;  M,  N,  tube  for  filling  and 
emptying  liquid  in  outer  jacket;  0,  air  outlet;  P,  dichotomous  branching  point 
of  inflow  tube;  Q  and  /?,  quadruple  branching  points  of  same;  S,  S',  wooden 
supports;  T,  thermometer.  At  each  of  the  points  H  and  K  the  blood  is  collected 
from  four  tubes  into  one,  bending  around  to  the  back,  and  there  redividing  into 
four  return  flow  tubes.  Arrows  show  the  direction  of  flow. 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   19 

economy  and  which  are  present  in  the  blood  in  only  minute 
quantity  at  any  one  time.  Among  these  as  yet  unidentified 
substances,  which  nevertheless  are  certainly  known  to  pass 
from  one  organ  to  others  via  the  blood,  are  all  of  the  so-called 
hormones,  the  active  principles  of  the  organs  of  internal  secretion. 
Of  these  organs  I  shall  presently  speak  more  in  detail. 

Our  present  methods  of  blood  analysis  give  us  litle  help  when 
we  endeavor  to  isolate  and  identify  one  of  these  elusive  yet  vitally 
important  principles,  not  to  mention  other  substances  of  the 
greatest  interest  arising  in  the  intermediary  stages  of  metabolism. 

Pondering  over  this  problem  it  occurred  to  me  that  possibly 
one  might  construct  an  apparatus  which  could  be  attached  to 
the  blood  vessels  of  a  living  animal  and  remove  from  the  blood 
flowing  through  it  all  traces  of  these  substances  as  fast  as  they  are 
poured  into  it,  without  at  the  same  time  removing  proteids  or 
the  indispensible  cellular  elements  (erythrocytes,  leucocytes, 
etc.),  of  the  blood.  Such  an  apparatus  might  conceivably  be 
employed  also  in  an  emergency  in  certain  toxic  states  in  which  the 
eliminating  organs,  more  especially  the  kidneys,  cannot  act 
rapidly  enough  to  relieve  the  system. 

An  apparatus  of  this  kind  was  constructed  with  the  skillful 
assistance  of  Dr.  Turner  and  is  shown  in  the  accompanying 
illustration.  (Fig.  3.)  Essentially,  the  method  consists  in  connect- 
ing an  artery  or  a  vein  of  the  animal  by  a  cannula  to  an  apparatus 
made  of  celloidin  or  other  dialyzing  membrane,  in  the  form  of 
tubes,  immersed  in  a  saline  solution  or  serum,  and  providing 
for  the  return  of  the  blood  to  the  animal's  body  by  another 
cannula  attached  to  a  vein.  The  tubes  and  cannulae  are  filled 
completely  before  attachment  with  a  saline  solution  which  ap- 
proximates in  composition  to  the  salt  content  of  the  serum  of 
the  animal.  This  is  displaced  into  the  body  by  the  inflow  of 
blood,  when  the  circulation  in  the  apparatus  is  established. 
The  blood  leaving  the  artery  flows  through  a  perfectly  closed 
system  and  returns  to  the  body  within  a  minute  or  two  without 
having  been  exposed  to  contact  with  the  air  or  any  chance  of 
microbial  infection,  while  the  diffusible  substances  which  it 
contains  can  pass  out,  more  or  less  rapidly,  through  the  walls  of 


20  JOHN    J.    ABEL 

the  tubes.  Coagulation  of  the  blood  is  prevented  by  injection 
of  hirudin.  We  have  named  the  process  "vividiffusion"  and 
the  apparatus  itself  constitutes  an  " artificial  kidney,"  as  it  were, 
but  differs  from  the  natural  organ  in  that  it  makes  no  distinction 
whatever  between  the  various  diffusible  constituents  of  the 
blood,  permitting  their  escape  from  the  celloidin  tubes  in  a 
manner  which  is  presumably  proportional  to  their  coefficients 
of  diffusion.  -As  you  are  well  aware,  the  natural  kidney  does 
not  ordinarily  allow  the  sugar  of  the  blood  to  escape  into  the 
urine,  its  excretory  function  is  elective  and  discriminatory. 
The  artificial  kidney,  as  just  stated,  makes  no  such  distinction. 
Sugar  is  eliminated  in  proportion  to  its  presence  in  the  blood 
equally  with  a  waste  product  like  urea.  We  have  it  in  our 
power,  however,  to  give  to  this  vividiffusion  apparatus  a  certain 
selective  ability,  at  least  in  the  sense  that  we  can  prevent  any 
given  substances,  as  sugar,  glycocoll,  and  the  like,  from  escap- 
ing from  the  blood,  by  the  simple  expedient  of  placing  an  equiva- 
lent quantity  on  the  outer  side  of  the  celloidin  tubes. 

With  this  apparatus  we  have  already  separated  from  the  blood 
a  number  of  constituents  which  cannot  be  obtained  with  equal 
ease  by  other  methods.  I  shall  not  here  enter  into  the  details 
of  the  chemical  methods  employed  in  differentiating  the  various 
constituents  of  the  dialysate,  but  will  merely  point  out  some  of 
the  results  that  we  have  obtained.14  It  has  been  found: 

(1)  That  the  non-protein  constituents   of  the  blood  can  be 
accumulated  in  any  desired  quantity  by  our  method,  the  quantity 
depending  on  the  extent  of  the  dialyzing  surface  of  our  apparatus 
and  the  number  of  experiments  made. 

(2)  That  the  rate   of  accumulation  of  various  nitrogenous 
substances  in  the  dialysate  and  their  relative  proportions  in  it 
do  not  differ  very  greatly  from  those  in  the  blood. 

(3)  That  alanine  and  valine  can  be  obtained  in  crystalline 
form;  that  histidine  and  creatinine  can  be  shown  by  reactions 
to  be  present. 

14  See  Jour,  of  Pharmacology  and  Experimental  Therapeutics,  vol.  5,  pp.  275- 
317,  and  625-641. 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   21 

(4)  Quite  recently  it  has  been  found  by  Dr.  Alice  Rohde, 
working  in  my  laboratory,  that  the  ammonia-yielding  substances 
of  the  blood  can  be  divided  into  two  classes  by  the  vividiffusion 
apparatus;   the   one,   comprised   of   diffusible   substances   only 
and  giving  off  their  ammonia  rapidly  and  completely  on  the 
addition   of   sodium   carbonate;   the   other,   non-diffusible   and 
therefore  not  escaping  through  our  apparatus,  and  characterized 
by  the  property  of  losing  their  ammonia  only  very  slowly  on  the 
addition  of  sodium  carbonate. 

(5)  By  means  of  our  method  of  vividiffusion  we  have  also 
found  that  oxyacids  circulate  in  the  blood  in  noticeable  proporr 
tion.     Lactic   acid  and   0-oxy  butyric   acid   in  particular  have 
been  identified  as  constituents  of  the  diffusate. 

(6)  From  the  residue  from  one  of  the  processes  employed  (that 
known  as  the  " ester  distillation")  I  obtained  a  crystalline  sub- 
stance having  the  composition,  C7H]2N2O2.     Dr.  Turner  and  I 
were  finally  enabled  to  identify  this  substance  as   a-isobutyl 
hydantoin  (1.  isobutyl  2.4.  diketo-tetrahydroimidazol)  first  pre- 
pared by  Pinner  and  Lifschiitz15  and  later  by  Fritz  Lippich16 
from  valeraldehydecyanhydrin  and  urea,   also  by  E.   Koenigs 
and   B.    Mylo17   from   dZ-leucinamid   and   ethylchlorcarbonate. 
I  suspect  that  other  hydantoins  are  present  in  the  fraction  from 
which  this  particular  hydantoin  was  isolated.     As   «-isobutyl 
hydantoin  is  the  first  of  its  class  to  be  isolated  from  an  animal 
fluid  or  tissue,  one  must  be  certain  that  the  substance  has  not 
been  formed  as  a  by-product  of  the  many  chemical  processes 
that  are  involved  in  obtaining  it;  in  other  words,  one  is  obliged 
to  prove  conclusively  that  the  substance  in  question  really  exists, 
as  such,  in  the  blood  of  the  dog.     For  the  present  we  can  not 
offer  this  final  proof.     Dr.  Turner,  however,  is  now  engaged  in 
searching  for  hydantoins  in  the  blood  of  the  pig  by  a  method 
that  will  remove  the  uncertainty  that  still  attaches  to  the  find 
as  it  now  stands. 

15  Ber.  d.  d.  chem.  Ges.,  20,  p.  2356  (1887). 

16  Ibid.,  41,  p.  2972  (1908). 

17  Ibid.,  41,  p.  4439  (1908). 


22  JOHN   J.    ABEL 

(7)  Certain  fractions  of  our  dialy sates,  those  derived  from  the 
so-called  "phosphotungstic  precipitate/'  have  not  yet  been  ana- 
lyzed in  detail,  owing  to  the  pressure  of  other  parts  of  the  prob- 
lem; it  is  apparent,  however,  that  we  are  dealing  with  an  indeter- 
minate number  of  substances,  and  it  is  more  than  probable  that 
some  hitherto  unidentified  constituents  of  the  blood  may  here 
be  found. 

Half  a  year  after  we  made  our  first  communication18  in  which 
it  was  announced  that  we  had  separated  from  our  dialysates  sev- 
eral grams  of  amino-acid  esters,  Abderhalden  published  a  paper19 
in  which  he  describes  the  separation  of  some  of  the  amino  acids 
from  large  quantities  of  blood  obtained  from  slaughter  houses. 
To  secure  the  small  amounts  of  amino  acids  needed  for  his 
identification  tests  this  investigator  was  obliged  to  use  at  one 
time  50  or  even  100  liters  of  beef  blood.  These  large  quantities 
of  blood  were  worked  up  partly  by  dialysis,  partly  by  precipi- 
tation methods  which  required  the  dilution  of  the  blood  by  many 
volumes  of  water.  The  method  of  vividiffusion  can  be  used  in 
the  most  scantily  equipped  laboratory  and  has  the  great  advan- 
tage of  separating  the  diffusible  substances  from  the  proteids 
of  the  circulating  blood  of  living  animals.  There  can  thus  be  no 
question  here  of  secondary  changes,  such  as  may  conceivably 
take  place  in  shed  and  coagulated  blood. 

I  come  now  to  a  newer  application  of  the  method  of  vivi- 
diffusion, one  to  which  I  alluded  a  few  moments  ago,  namely  its 
possible  employment  to  abstract  from  the  circulating  blood 
certain  hormones  or  products  of  internal  secretion  in  amounts 
that  will  suffice  for  pharmacological  study,  if  not  for  chemical 
analysis.  This  application  is  still  in  its  very  beginning,  many 
difficulties  yet  remain  to  be  surmounted,  and  I  speak  of  it  here 
only  because  it  leads  me  quite  naturally  to  a  field  of  study  which 
is  of  the  greatest  importance,  a  field  which  at  present  is  ripe 

18  On  the  removal  of  diffusible  substances  from  the  circulating  blood  by  means 
of  dialysis,  Trans.  Assoc.  Americ.  Physicians.,  May,  1913.    Also  demonstration 
of  our  apparatus  before  the  pharmacological  section,  Int.  Med.  Congress  at  Lon- 
don, August,  1913. 

19  Zeitschr.  f.  physiol.  Chemie.,  vol.  88,  p.  478,  Dec.  23,  1913. 


EXPERIMENTAL   AND   CHEMICAL   STUDIES   OF   THE    BLOOD      23 

for  the  methods  of  the  chemical  explorer.  I  refer  to  the  explora- 
tion of  the  organs  of  internal  secretion,  especially  to  the  study 
by  chemical  methods  of  their  specific  products.  In  attempting 
this,  a  vividiffusion  apparatus  of  the  proper  sort  is  attached  to 
the  veins  of  a  particular  organ,  as  the  thyroid  gland,  and  the 
diffusate  thus  obtained  is  studied  by  pharmacological  and 
chemical  methods.  This  diffusate  must  also  be  compared  in 
respect  to  its  pharmacological  properties,  at  least,  with  both 
the  arterial  and  the  venous  blood  of  the  gland  under  investiga- 
tion. But  whatever  may  be  the  outcome  of  such  studies  I  hope 
to  make  it  evident  to  you  in  what  I  am  about  to  say  that  we  are 
here  dealing  with  matters  of  the  greatest  importance  to  biology 
and  medicine. 

III.  THE  BLOOD  AND  THE  SPECIFIC  SECRETORY  PRODUCTS  OF 
THE  ORGANS  OF  INTERNAL  SECRETION 

In  this  field  we  touch  on  the  one  hand  upon  knowledge  which 
is  deeply  rooted  in  the  earliest  practical  experience  of  mankind, 
and  on  the  other  on  the  results  of  epoch-making  clinical  observa- 
tions and  of  experimentation  in  scientific  laboratories  up  to  the 
present  moment.  Man  has  long  made  practical  use  of  the  fact 
that  the  removal  of  the  sex  glands  at  a  certain  age  will  give  us 
the  docile  ox  in  place  of  the  unruly  bull,  the  easily  fattened  and 
tender-fleshed  capon  for  the  muscular  and  stringy  cock;  and 
human  society  in  its  various  stages  of  development  has  also  prac- 
ticed this  mutilation  on  its  individuals  for  various  reasons, 
religious,  economic  or  penal.  The  sale  of  eunuchs  in  Bagirmi 
and  other  parts  of  North  Central  Africa  still  continues,  we  are 
told,  and  it  was  only  on  the  accession  of  Pope  Leo  XIII  in 
1878  that  the  practice  of  castrating  boys  in  order  to  furnish  the 
Sistine  Choir  its  famous  adult  soprano  voices  was  discontinued. 

From  remote  antiquity,  therefore,  man  has  known  that  the 
gonads,  or  sex  glands,  exert  a  marked  influence  on  the  develop- 
ment and  structure  of  the  body,  but  until  recent  times  there  has 
existed  no  valid  explanation,  no  correct  theory  of  their  relation- 
ship to  the  rest  of  the  body.  It  is  true,  there  were  not  wanting 


24  JOHN   J.    ABEL 

acute  minds  whose  attempted  explanation  came  close  to  the 
truth,  but  experimental  proof  was  lacking.  We  gather  from 
Aesop's  fable  that  it  will  not  do  for  the  various  members  of  the 
body  to  fall  out  with  one  another,  and  the  medicine  of  an  older 
time  has  long  used  the  expression  consensus  par  Hum  as  indicating 
the  interrelationship  of  the  various  organs.  Even  in  quite 
modern  times  this  consensus  of  the  various  organs  was  supposed 
to  be  entirely  effected  through  the  intermediation  of  the  nerv- 
ous system,  a  view  tersely  expressed  by  Cuvier  when  he  said, 
"Le  systeme  nerveux  est,  au  fond,  tout  1'animal,  les  autres 
systemes  ne  sont  la  que  pour  le  servir." 

Side  by  side  with  this  view  of  the  preponderating  rdle  of  the 
nervous  system  we  find  the  old  humoral  doctrine,  having  ob- 
tained new  support  in  Harvey's  discovery  of  the  circulation, 
struggling  to  prove  the  importance  of  the  blood  stream  for  the 
interrelationship  of  the  organs.  In  1775,  Theophile  de  Bordeu20 
of  Montpellier  and  later  Paris,  a  fashionable  practitioner  with 
considerable  knowledge  of  anatomy,  propounded  the  doctrine  that 
every  organ  lives  its  own  life  and  is  the  source  of  specific  chemical 
substances  (humeurs  particulieres)  which  are  yielded  up  to 
the  blood  and  which  are  necessary  to  the  integrity  of  the  body. 
The  idea  that  every  organ  has  its  own  special  life  is  repeated 
again  and  again  in  Bordeu's  writings: 

It  must  be  remembered  that  each  organic  part  of  the  living  organism 
has  its  own  manner  of  existence,  of  acting,  of  feeling  and  of  moving : 
each  has  its  own  particular  savor,  structure,  external  and  internal 
make  up,  odor,  weight,  manner  of  growth,  of  expanding  and  con- 
tracting; each  competes  after  its  own  manner  and  for  its  share  in  the 
ensemble  of  all  the  functions,  in  the  general  life:  each  organ,  in  brief, 
has  its  own  life  and  its  own  functions  quite  distinct  from  all  others.21 

From  the  organs  the  blood  derives  a  multitude  of  humors  and 
"emanations"  (nuees  d'e*manations  qui  composent  et  animent  le 
sang). 

20  See  his  Recherches  anatomiques  sur  la  position  des  glandes  et   sur  leur 
action,  Paris,  1752;  and  his  Analyse  medicinale  du  sang,  1776. 

21  P.  942,  Analyse  medicinale  du  sang,  vol.  2,  oeuvres  completes  de  Bordeu 
edited  by  Richerand,  Paris,  1818. 


EXPERIMENTAL  AND    CHEMICAL   STUDIES   OF   THE    BLOOD       25 

Comparable  at  bottom  to  fecundated  white  of  egg,  the  blood  (a  fluid 
tissue  which  fills  the  vessels  of  the  body),  is  animated  by  the  semen, 
that  is  to  sav,  it  contains  a  certain  quantity  of  seminal  emanations 
which  vivify  it;  it  contains  in  the  same  way  a  portion  of  the  bile,  and 
also  a  portion  of  the  milky  juices,  especially  in  infancy  and  in  women 
at  the  time  of  pregnancy;  it  contains  a  colored  part  which  is  elaborated 
in  the  entrails;  it  has  serosity  in  abundance;  it  contains  an  extract  of 
each  glandular  organ  which  contributes  its  share  to  the  emanations  in 
which  all  the  solid  parts  (of  the  blood)  swim;  a  certain  quantity  of  air; 

a  portion  of  mucous  substance.     ...     22 
* 

Bordeu's  theories  in  respect  to  the  diseases  that  are  conse- 
quent to  a  superabundance  or  wrong  admixture  of  these  various 
special  principles  or  emanations,  his  various  cachexias  (cachexie 
bileuse,  albumineuse,  etc.),  cannot  be  considered  here. 

Three-quarters  of  a  century  after  Bordeu,  in  1849,  we  find  a 
German  professor  of  physiology,  in  Gottingen,  A.  A.  Berthold, 
giving  the  first  experimental  proof  of  the  correctness  of  this 
theory.  This  experimenter,  in  a  beautifully  concise  monograph 
of  only  four  pages,  describes  his  experiments  upon  young  cock- 
erels. By  removing  the  sex  glands  from  their  normal  position 
and  transplanting  them  to  another  part  of  the  body  (to  the 
outer  surfaces  of  the  intestine  in  the  peritoneal  cavity),  where 
it  was  impossible  for  them  to  expel  a  secretion  or  to  play  any 
external  role  as  sex  glands,  he  was  able  to  prove  that  these  glands 
have  two  functions,  (a)  the  well-known  reproductive  function, 
and  (b)  an  important  function  in  maintaining,  as  he  says,  the 
"consensus  partium."  Such  cockerels  did  not  show  the  changes 
that  were  seen  in  the  castrated  bird;  on  the  contrary,  they  devel- 
oped into  the  usual  type,  remaining  male  birds  in  respect  to  their 
vocal  capacity,  their  desire  for  battle,  the  growth  of  comb  and 
wattles  and  the  sexual  instinct.  Berthold  draws  the  conclusion 
from  his  experiments  that  the  generative  organs  influence  the 
consensus  partium  by  acting  upon  the  blood  and  through  this 
upon  the  organism  as  a  whole. 

The  observations  of  Berthold  were  forgotten  and  even  dis- 
credited (Rudolf  Wagner)  and  they  had  no  influence  apparently 

22  P.  1006,  Ibid. 


26  JOHN   J.    ABEL 

on  the  development  of  work  in  this  field  during  the  following- 
half  century. 

I  cannot  leave  this  part  of  my  subject  without  mentioning 
the  work  of  the  great  Frenchman,  Claude  Bernard,  whose  dis- 
covery of  glycogen  in  the  liver  and  elsewhere  must  always  rank 
as  one  of  the  great  discoveries  of  physiology.  With  perfect 
justice  Bernard  declared  that  the  conversion  of  glycogen  into 
sugar  and  the  passage  of  the  latter  into  the  blood  constitutes 
the  internal  secretion  of  the  liver  while  the  bile  constitutes  its 
external  secretion. 

One  other  investigator,  the  modern  pioneer  in  this  field,  a 
restless  spirit,  a  man  of  enthusiasm,  possessing  an  original 
mind  of  a  high  order,  one  who  is  of  especial  interest  to  Americans, 
cannot  be  passed  by  without  mention.  Charles  Edward  Brown- 
Sequard  was  born  at  Port  Louis,  Mauritius,  on  the  8th  of  April, 
1817.  His  father  was  an  American,  his  mother  a  French  woman, 
but  he  himself,  it  is  stated,  always  wished  to  be  regarded  as  a 
British  subject.  After  a  varied  career  in  four  countries  (England, 
France,  Mauritius  and  the  United  States),  having  held  the  chair 
of  physiology  in  Harvard  from  1864  to  1867,  he  finally,  in  1878, 
succeeded  Claude  Bernard  as  professor  of  experimental  medicine 
in  the  College  de  France,  where  he  remained  until  his  death  in 
1894. 

As  far  back  as  1869  Brown-Sequard  took  the  position  in  his 
lectures  in  Paris  that  all  glandular  organs,  irrespective  of  whether 
they  possess  external  excretory  ducts  or  not,  give  off  to  the 
blood  substances  which  are  useful  and  necessary  for  the  body  as 
a  whole,  an  opinion,  as  we  have  seen,  that  had  already  been 
stated  by  Theophile  de  Bordeu  in  1775.  He  even  made  experi- 
ments on  himself  with  a  testicular  extract,  and  the  meeting  of 
the  Paris  Socie*te*  de  Biologie,  June  1,  1889,  at  which  Brown- 
Sequard,  then  72  years  old,  made  his  report  on  these  experiments, 
Biedl  calls  "the  true  birthday  of  the  doctrine  of  internal  secre- 
tion." 

From  this  time  an  ever  increasing  army  of  experimental 
laboratory  workers  have  been  engaged  in  this  field.  Their 


EXPERIMENTAL   AND    CHEMICAL    STUDIES    OF    THE    BLOOD       27 

names  even  cannot  here  be  given,  neither  can  I  go  into  detail 
with  regard  to  the  great  and  fundamental  contributions  that 
have  been  made  by  medical  clinicians,  surgeons  and  anatomists, 
as  Basedow,  Graves,  Addison,  Marie,  Gull,  Ord,  Kocher,  Rever- 
din,  Minkowski,  Von  Mering,  Sandstrom  and  others,  to  name 
only  some  of  the  leaders  of  the  immediate  past,  not  to  speak 
of  the  excellent  contributions  that  have  been  made  in  recent 
years  by  our  own  surgeons  and  internists. 

And  so  there  has  gradually  come  into  existence  an  enormous 
store  of  facts,  physiological,  pathological,  chemical  and  clinical, 
in  regard  to  a  number  of  structures  that  are  classed  as  endocrinous 
glands  or  organs  of  internal  secretion. 

What  is  meant  today  by  this  term,  products  of  internal  secre- 
tion, and  what  organs  furnish  principles  that  can  be  classed  as 
internal  secretions? 

For  the  present  we  shall  follow  custom  and  apply  the  term 
to  definite  and  specifically  acting  indispensable  chemical  products 
of  certain  organs  (organs  that  may  or  may  not  have  an  external 
secretion),  which  are  poured  into  the  blood  and  modify  the  develop- 
ment and  growth  of  other  organs,  more  especially  during  embryonic 
and  early  life,  and  which  also  greatly  affect  the  entire  metabolism, 
that  of  the  nervous  system  included,  during  adult  life.  I  regard 
it  as  not  unlikely  that  with  the  growth  of  knowledge  of  the 
chemistry  of  the  animal  organism  we  shall  drop  the  term  entirely. 
We  have  already  seen  that  the  liver,  according  to  Claude  Ber- 
nard's view,  has  an  internal  secretion,  yet  this  gland  is  not  usually 
classed  with  the  endocrinous  organs.  In  a  sense,  too,  as  has  been 
frequently  pointed  out,  every  cell  of  the  body  furnishes  in  the 
carbon  dioxide  which  it  eliminates  a  hormone  or  product  of  inter- 
nal secretion,  since  under  normal  conditions  the  carbon  dioxide 
of  the  blood  is  one  of  the  chief  regulators  of  the  respiratory  center, 
influencing  this  center  by  virtue  of  its  acidic  properties.  These 
and  other  instances  that  could  be  given  show  that  the  term  inter- 
nal secretions  could  be  greatly  extended  in  its  scope,  but  in  the 
present  state  of  our  knowledge  it  is  convenient  to  limit  it  to  the 
products  of  a  certain  number  of  glands. 


28  JOHN   J.    ABEL 

The  generally  accepted  list  of  the  organs  of  internal  secretion 
is  as  follows,  though  even  at  this  moment  a  foreign  investigator23 
is  asking  us  to  accept  certain  newly  discovered  small  structures 
located  in  the  neck  as  belonging  to  our  list:  the  thyroid,  para- 
thyroid, thymus,  hypophysis  cerebri,  epiphysis  cerebri,  pan- 
creas, mucosa  of  the  duodenum,  the  two  adrenal  systems  (the 
chromaphil  tissue  and  the  interrenal  bodies)  and  the  gonads,  or 
sex  glands. 

Permit  me  to  give  you  a  few  illustrations  of  the  derangement 
of  health  and  bodily  structure  that  follow  upon  the  removal  or 
disease  of  these  glands.  Many  of  you  have  doubtless  seen 
these  illustrations,  but  I  am  giving  them  here  for  the  benefit 
of  those  who  have  never  been  given  proof  of  the  great  significance 
of  these  glands  in  order  that  they  may  have  a  background  of 
fact  for  the  better  apprehension  of  certain  chemical  questions 
which  I  wish  presently  to  bring  to  your  notice. 

Figure  4  is  an  illustration  taken  from  a  well-known  paper  of 
the  Viennese  surgeon,  A.  v.  Eiselsberg,  in  which  he  describes 
the  effects  of  removing  the  thyroid  gland  from  young  goats. 
The  two  animals  here  shown  are  of  the  same  age  and  parentage. 
On  the  twenty-first  day  after  birth  v.  Eiselsberg  removed  the 
thyroid  gland  from  one  of  them.  The  incision  healed  by  primary 
intention.  After  three  weeks  the  control  animal  began  to  out- 
grow the  one  operated  upon  and  when  four  months  old  the  animals 
presented  the  appearance  here  shown.  The  goat  with  thyroid 
removed  has  shortened  extremities,  a  shortened  skull  and  an 
altered  pelvis  due  to  a  delayed  ossification  at  the  epiphyseal  line. 
The  wool  of  this  animal  is  longer  and  easily  torn  out  by  the 
handful,  the  sex  glands  are  atrophied,  the  hypophysis  is  enlarged, 
the  intelligence  is  lowered;  in  brief,  a  chronic  pathological  con- 
dition is  produced  in  this  experiment  which  finds  an  analogy  in 
human  beings  and  is  known  as  cachexia  thyreopriva.  We  can- 
not enter  into  further  details,  but  I  may  remark  that  the  results 
obtained  in  such  removal  experiments  vary  greatly  with  the 
age  and  with  the  species  of  animal  used. 

23  Ueber  erne  neue  Druse  mit  innerer  Sekretion  (Glandula  insularis  cervicalis) . 
N.  Pende;  Arch.  f.  mikroscop.  Anat.,  vol.  86,  p.  193,  1914. 


FIG.  4.     INFLUENCE  OF  THE  THYROID  GLAND 

ON  GROWTH. 

The  animals  are  four  months  old.  The  one 
on  the  right  had  the  thyroid  removed  on  the 
21st  day  after  birth.  Taken  from  v.  Eiselsberg. 


FIG.  5.     GIRL  THIRTEEN   YEARS  OLD.     CASE 

OF  CONGENITAL  MYXOEDAMA.    From 

v.  Eiselsberg. 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   29 

In  figure  5  we  have  the  results  of  a  similar  experiment  which 
nature  herself  has  performed  for  us.  The  child  here  shown  is  a 
13-year-old  idiotic  myxoedematous  dwarf  whose  general  symp- 
toms point  to  a  congenital  absence  of  the  thyroid  gland.  Investi- 
gators have  proved  this  to  be  the  true  cause  by  anatomical  studies 
of  the  bodies  of  other  congenital  myxoedematous  children  of  this 
class. 

[Further  illustrations  were  then  given  by  means  of  lantern  slides 
of  endemic  cretinism  and  goitre  and  it  was  shown  by  statistics  and  by 
a  map  of  Europe  that  these  abnormalities  have  very  great  economic 
significance,  on  account  of  their  prevalence  in  certain  parts  of 
central  and  western  Europe  and  to  a  less  degree  in  our  own  and  other 
countries.  For  instance  in  Switzerland  one-sixth  of  the  male  popula- 
tion is  unfitted  for  military  service  by  cretininism  in  some  degree.24 

Pictures  of  persons  suffering  from  other  disorders  as  exophthalmic 
goitre,  acromegaly  or  giantism  and  parathyroid  tetany  were  also 
given  with  a  brief  statement  of  the  glandular  and  general  nutritive 
changes  involved.  Animals  such  as  the  monkey,  the  dog,  the  rat 
and  others  are  likewise  subject  to  diseases  of  this  gland.] 

After  even  these  few  illustrations  of  abnormalities  that  follow 
on  removal  or  disease  of  these  glands,  I  think  you  will  agree  with 
me  that  my  colleague,  Professor  Barker,  has  not  exaggerated 
their  importance  when  he  says, 

More  and  more  we  are  forced  to  realize  that  the  general  form  and 
the  external  appearance  of  the  human  body  depend  to  a  large  extent 
upon  the  functioning,  during  the  early  developmental  period  (and  later) , 
of  the  endocrine  glands.  Our  stature,  the  kinds  of  faces  we  have,  the 
length  of  our  arms  and  legs,  the  shape  of  the  pelvis,  the  color  and  con- 
sistency of  our  integument,  the  quantity  and  regional  location  of  our 
subcutaneous  fat,  the  amount  and  distribution  of  hair  on  our  bodies, 

24  Der  Kretinismus,  H.  Vogt  in  Handbuch  der  Neurologic  (Lewandowsky) , 
vol.  iv,  Spezielle  Neurologie  iii,  p.  139.  Here  also  it  is  stated  that  the  three 
Italian  provinces,  Piedmont,  Lombardy  and  Venice  had  120,000  cases  of  goitre 
and  13,000  cretins  in  1883,  the  total  population  of  these  provinces  at  that  time 
being  9,400,000.  In  1908,  according  to  Biedl,  Austria  had  on  the  average  64  cre- 
tins to  every  100,000  of  the  population.  In  1873  France  had  120,000  cretins  in 
Savoy,  the  Maritime  Alps  and  the  Pyrenees.  It  will  be  seen  that  the  thyreo- 
pathies  constitute  a  heavy  drain  on  the  resources  of  European  people. 


30  JOHN   J.    ABEL 

the  tonicity  of  our  muscles,  the  sound  of  the  voice  and  the  size  of  the 
larynx,  the  emotions  to  which  our  exterieur  gives  expression — all  are 
to  a  certain  extent  conditioned  by  the  productivity  of  our  hormono- 
poietic  glands.  We  are  simultaneously,  in  a  -sense,  the  beneficiaries 
and  the  victims  of  the  chemical  correlations  of  our  endocrine  organs.25 

I  cannot  here  take  up  questions  of  therapeutics  in  this  interest- 
ing field.  I  can  only  say  that  aside  from  surgical  intervention 
and  the  brilliant  results  of  thyroid  treatment  in  cases  once  utterly 
hopeless,  we  have  little  to  offer  that  has  been  positively  estab- 
lished. Nor  shall  I  attempt  to  discuss  the  interrelationship  of 
these  glands.  It  has  become  increasingly  evident  that  to  touch 
one  of  them  is  to  touch  all.  Various  writers  have  endeavored 
to  express  this  interrelationship  in  a  series  of  charts  or  diagrams. 
Of  these  diagrams  D.  Noel  Paton  has  well  said:26 

They  may  well  be  a  grotesque  parody  of  what  will  ultimately  be 
found  to  be  the  relationship  of  the  activities  of  these  organs.  They 
are  probably  as  near  the  truth  as  those  quaint  ancient  maps  of  the  Inr 
dies  with  their  'here  be  gold'  scrawled  across  them  which  served  as 
the  charts  of  our  forefathers,  and  if,  like  them,  they  merely  indicate 
the  direction  which  further  investigation  should  take  and  suggest 
lines  of  attack,  they  will  have  served  their  purpose. 

Notable  and  well  established,  apparently,  is  the  relationship 
existing  between  the  gonads,  the  thyroid  and  thymus  glands, 
the  hypophysis  and  suprarenal  glands.  Very  difficult  is  it  also 
to  unravel  the  relationship  of  the  interval  secretions  as  a  whole 
to  the  nervous  system,  both  central  and  peripheral. 

In  view  of  the  fact  that  we  so  little  understand  the  chemical 
principles  elaborated  in  these  organs  and  discharged  by  them 
into  the  blood  whereby  the  remarkable  changes  described  above, 
are  effected,  it  is  evident  that  further  progress  now  waits  on 
chemical  discoveries. 

The  only  fairly  complete  chemical  work  yet  done  on  any  of 
these  organs  is  that  on  the  suprarenal  glands.  These  organs 

25  On  abnormalities  of  the  endocrine  functions  of  the  gonads  of  the  male, 
Am.  Jour.  Med.  Sciences,  vol.  149,  p.  1,  1915. 

26  Regulators  of  Metabolism,  p.  183,  Macmillan  &  Co.,  London,  1913. 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   31 

are  two  flattened,  ductless,  yellow-brown  glands,  each  of  which 
is  loosely  attached  to  the  anterior  and  inner  part  of  the  summit 
of  the  corresponding  kidney.  The  normal  gland  of  a  healthy 
man  weighs,  according  to  Elliot,27  between  4  and  5  grams,  and 
contains  4  or  5  mgm.  of  the  characteristic  principle  concerning 
which  I  shall  speak  in  a  moment.  These  organs  are  essential 
to  life;  their  destruction  in  man  by  tubercular  and  more  rarely 
by  other  processes  leads  to  a  chronic  condition  characterized 
by  gastro-intestinal  symptoms,  great  muscular  weakness  and  a 
bronzing  of  the  skin  and  mucous  membranes,  this  whole  symp- 
tom complex  being  known  as  Addison's  disease  (1855).  In  man 
and  the  higher  animals  generally  this  organ  is  a  double  structure 
in  which  two  parts  which  are  quite  separate  and  totally  different 
in  lower  forms,  as  in  the  elasmo-branch  and  teleostean  fishes, 
are  united  in  such  a  manner  that  one  constitutes  the  medulla 
and  the  other  the  cortex  of  the  gland,  the  latter  completely 
enclosing  the  former. 

The  cortical  part  of  the  gland  is  called  by  histologists  the  inter- 
renal  tissue.  Biedl  has  shown  that  when  this  tissue  is  removed 
from  selachians  (where,  as  just  stated,  it  constitutes  a  separate 
organ)  the  animal  gradually  weakens,  no  longer  takes  food  and 
dies  in  fourteen  to  eighteen  days.  Still  other  experiments  demon- 
strate that  this  cortical  part  of  the  gland  exerts  great  influence 
on  bodily  growth  and  sexual  development.  Numerous  researches 
of  a  chemical  character  have  been  carried  out  on  this  part  of 
the  gland,  especially  in  respect  to  its  lipoid  content.  Last 
year,  Voegtlin  and  Macht28  isolated  from  it  and  also  from  blood 
serum  a  new  crystalline  substance  which  has  a  vaso-constricting 
action  on  the  blood  vessels  and  a  digitalis-like  action  on  the 
heart.  This  has  been  decided  to  be  a  lipoid  closely  related  to 
cholesterin.  As  we  are  entirely  ignorant  of  the  means  by  which 
the  adrenal  cortex  exerts  its  profound  influence  on  the  body, 

27  Death  and  the  adrenal  gland,  Quart.  Jour,  of  Medicine,  vol.  8,  p.  47,  1914. 
An  interesting  paper  by  E.  R.  Weidlein,  a  fellow  of  the  Mellon  Institute,  on  the 
adrenal  glands  of  the  whale  will  be  found  in  the  Jour,  of  Industrial  and  Engi- 
neering Chemistry,  vol.  4,  No.  9,  Sept.,  1912. 

28  Isolation  of  a  new  vasoconstrictor  substance  from  the  blood  and  the  adrenal 
cortex,  Jour.  Amer.  Med.  Assoc.,  vol.  61,  p.  2136,  1913. 


32  JOHN   J.    ABEL 

the  isolation  of  this  substance  is  of  especial  interest.  For  the 
present  we  cannot  state  whether  it  represents  one  or  all  of  the 
products  of  the  internal  secretion  of  the  cortex,  or  whether  in- 
deed it  has  any  connection  at  all  with  the  function  of  the  gland. 

The  medullary  portion  consists  of  cell  groups  which  assume 
a  brown  color  when  treated  with  chromic  acid  or  dichromates, 
in  consequence  of  the  reduction  of  these  compounds  to  brownish 
or  reddish-brown  basic  chromates.  For  this  reason  it  has  been 
designated  the  chromaphil  tissue.  Now  such  chromaphilic  cell 
groups  are  not  confined  to  the  medulla  of  the  suprarenal  gland 
but  are  also  found  lying  alongside  the  abdominal  aorta,  in  the 
carotid  gland  and  in  the  sympathetic  system. 

It  was  known  to  earlier  experimenters  that  aqueous  extracts 
of  the  entire  capsules  were  highly  toxic  to  animals  when  injected 
directly  into  the  circulation,  but  it  remained  for  Oliver  and 
Schafer  in  1894  to  demonstrate  that  extracts  of  the  medullary 
part,  in  the  most  minute  quantity,  cause  a  marked  rise  in  blood 
pressure  and  greatly  stimulate  the  heart.  In  1897  I  showed 
that  the  substance  responsible  for  these  actions  could  be  isolated 
from  the  glands  in  the  form  of  a  benzoyl  compound.29  Salts  of 
a  base  obtained  by  saponifying  this  benzoyl  derivative  were 
shown  by  me  (1898)  to  possess  the  characteristic  chemical  and 
physiological  properties  of  the  gland  itself.  To  the  principle 
thus  isolated  I  gave  the  name  epinephrin.  Very  soon  after 
this  v.  Furth  (1899-1900)  isolated  the  principle  under  discussion 
in  the  form  of  an  amorphous  indigo-colored  iron  compound, 
and  in  1901,  Takamine  and  Aldrich  succeeded,  independently, 
in  precipitating  the  native  substance  with  the  help  of  ammonia, 
and  without  first  subjecting  it  to  the  more  complicated  processes 
which  had  been  used  by  myself  some  years  before. 

These  results  were  soon  followed  by  the  brilliant  researches 
of  a  number  of  organic  chemists,  Dakin,  Jowett,  Pauly  and  Fried- 
mann,  which  culminated  in  the  synthetic  production,  first,  of 
the  racemic  form  by  Stolz  in  1906,  and  later  of  the  laevorotatory 
form  by  Flacher  in  1908,  the  form  in  which  the  substance  exists 

29  For  literature  see  Abel  and  Macht:  Jour,  of  Pharmacol.  and  Exp.  Therapeu- 
tics, vol.  3,  p.  327,  1912. 


EXPERIMENTAL   AND   CHEMICAL   STUDIES   OF   THE   BLOOD      33 

in  the  gland  itself.  The  chemical  history  of  this  remarkable 
blood-pressure-raising  constituent  which  is  found  wherever 
chromaphil  tissue  is  encountered  is  therefore  now  a  closed  chap- 
ter. We  are  no  longer  dependent  upon  the  glands  of  the  ox 
or  the  sheep  for  its  preparation  for  the  many  uses  to  which  it  is 
put  by  the  medical  specialist,  the  surgeon  and  the  general  prac- 
titioner, but  shall  always  be  able  to  produce  it  in  our  laboratories 
as  long  as  coal  tar  remains  at  our  disposal.  In  chemical  language 
it  is  described  as  a  di-hydroxymethyl-aminoethylol  benzene,  or 
more  concisely  and  simply,  it  is  an  aromatic  amino  alcohol. 
It  is  as  noteworthy  for  its  instability  in  solution  as  it  is  remarkable 
for  its  physiological  properties.  It  is  a  true  product  of  internal 
secretion  and  can  apparently  be  detected  in  the  venous  blood  of 
the  adrenal  glands.30  I  shall  not  further  describe  its  chemical 
properties,  but  would  call  your  attention  to  the  fact  that  in  at 
least  one  animal,  a  tropical  toad,  Bufo  agua,  this  principle  occurs 
also  as  a  constituent  of  an  external  secretion. 

The  toad  I  may  say  here  has  a  very  interesting  history.31 
It  has  been  regarded  from  the  earliest  times  as  a  poisonous  ani- 
mal and  various  races,  including  our  own,  have  long  made  medi- 
cinal use  of  its  skin.  The  Chinese  to  this  day  use  as  a  cure  for 
dropsy  a  preparation  derived  from  toad  skin,  called  senso. 
Among  western  nations  it  has  always  been  a  folk's  remedy  and 
almost  up  to  the  time  of  the  introduction  of  digitalis  (1775)  as 
a  medical  agent  our  very  best  medical  authorities  used  these 
skins  in  cases  of  dropsy.  Dr.  Langworthy,  Department  of  Agri- 
culture, Washington,  has  given  me  the  following  recipe  for  mak- 
ing a  toad  ointment  which  was  in  use  among  our  early  New 
England  colonists  for  the  treatment  of  sprains  and  rheumatism. 
Toad  Ointment:  Good  sized  live  toads,  4  in  number:  put  into 
boiling  water  and  cook  very  soft;  then  take  them  out  and  boil 
the  water  down  to  |  pint,  and  add  fresh  churned,  unsalted  but- 

30  It  has  not  been  conclusively  shown  that  the  blood  pressure-raising  consti- 
tuent of  this  blood  is  really  epinephrin  (adrenalin)  and  not  an  alteration  product. 

31  Abel  and  Macht:  The  poisons  oi  the  tropical  toad,  Bufo  agua,  Jour.  Amer. 
Med.  Assoc.,  vol.  56,  p.  1531,  1911,  and  two  crystalline  pharmacological  agents 
obtained  from  the  tropical  toad,  Bufo  agua,  Jour.  Pharmacol.  and  Exp.  Thera- 
peutics, vol.  3,  1319,  1912. 


34  JOHN   J.    ABEL 

ter  1  pound  and  simmer  together;  at  the  last  add  tincture  of 
arnica  2  ounces. 

The  particular  toad,  Bufo  agua,  to  which  I  have  referred,  is 
of  further  interest  because  the  aborigines  of  the  Upper  Amazon 
make  an  arrow  poison  from  the  creamy  secretion  that  exudes 
from  its  skin  glands  when  it  is  irritated  or  overheated,  a  poison 
so  powerful  that  it  kills  in  a  few  moments  large  game,  such  as 
the  stag  or  the  jaguar. 

Two  years  ago  I  was  examining  a  specimen  of  this  giant 
among  toads  when  I  noticed  that  this  creamy  secretion  made  on 
a  scalpel  a  peculiar,  greenish  blue  discoloration.  I  at  once 
remembered  where  I  had  seen  this  color  years  before  on  a  scalpel 
used  in  cutting  into  the  medulla  of  a  suprarenal  gland.  Work- 
ing from  this  hint  I  was  soon  able  to  isolate  the  now  familiar 
substance,  adrenalin  or  epinephrin,  from  this  toad's  glands. 
Scientists  have  been  not  a  little  surprised  to  learn  that  this 
substance  is  present  in  very  large  amounts  in  the  skin  of  this 
tropical  toad.  It  is  not  found  in  the  skin  of  the  common  Ameri- 
can toad. 

I  also  succeeded  in  isolating  the  principle  to  which  the  toad 
skin  owes  its  curative  power  for  dropsy,  a  very  different  princi- 
ple from  epinephrin.  It  has  been  obtained  in  the  form  of  beauti- 
ful crystals  and  has  the  composition  represented  by  the  formula, 
Ci8H24O4,  and  has  been  named  bufagin. 

Just  as  in  the  case  of  bleeding,  we  have  here  another  instance 
of  the  every  day  observation  of  mankind  justified  by  science. 
That  powdered  toad  skin  could  cure  dropsy  has  been  ridiculed 
by  the  learned  for  a  century,  and  now  we  possess  in  bufagin  and 
in  the  slightly  different  bufotalin,  which  has  only  recently  been 
obtained  in  crystalline  form  from  the  skin  of  the  common  Euro- 
pean toad,  the  actual  proof  of  the  correctness  of  the  old  belief. 

We  are  now  studying  the  chemical  constitution  of  bufagin  in 
my  laboratory,  and  although  this  problem  is  one  of  great  diffi- 
culty, we  hope  nevertheless  that  our  work  will  throw  some 
light  on  the  fundamental  chemical  properties  of  cardiac  stimu- 
lants. We  now  also  understand  why  the  secretion  of  the  skin 
of  Bufo  agua  may  be  used  as  an  arrow  poison,  since  it  contains 


EXPERIMENTAL   AND    CHEMICAL    STUDIES    OF   THE   BLOOD      35 

these  two  powerful  drugs,  epinephrin  and  bufagin,  which  in 
overdose  act  fatally  on  the  heart  and  blood  vessels. 

We  cannot  leave  the  consideration  of  this  subject  without 
noting  the  influence  that  the  study  of  the  pharmacological 
properties  of  epinephrin  has  exerted  on  certain  departments 
of  medical  science. 

Chromaphilic  cells  of  the  body,  whether  located  in  the  medul- 
lary portion  of  the  suprarenal  gland,  or  elsewhere,  all  yield  epine- 
phrin and  modern  studies  have  shown  that  these  chromaphilic 
cells  are  intimately  related  to  the  sympathetic  nervous  system 
in  their  origin,  and  have  differentiated  themselves  from  it.  We 
are  not  surprised,  therefore,  to  find  that  epinephrin,  the  secre- 
tory product  of  these  cells,  has  an  elective  affinity  for  the  sym- 
pathetic nervous  system,  the  thoracico-abdominal  part  of  the 
antonomic  system.  The  well  known  symptoms  that  follow 
upon  the  administration  of  epinephrin;  extreme  vaso-constriction, 
tachycardia,  dilatation  of  the  pupil,  inhibition  of  peristaltic 
movement  in  the  alimentary  canal,  contraction  of  the  pyloric 
and  ileo-coecal  sphincters,  increased  motility.  of  the  pregnant 
uterus  and  glycosuria  have  all  been  shown  to  be  due  to  the 
fact  that  this  hormone  stimulates  and  sensitizes  the  sympathetic 
myoneural  and  adenoneural  junctions  or  terminations  of  the 
sympathetic  nervous  system.  Numerous  experiments  have 
shown  that  the  changes  induced  by  epinephrin  in  the  activity 
of  various  organs  which  are  innervated  by  the  sympathetic 
nervous  system  are  in  all  respects  like  those  that  are  brought 
about  by  electrical  stimulation  of  this  system,  and  it  is  apparent 
that  such  experiments  have  already  assisted  in  elucidating  many 
obscure  points  in  the  functional  activity  of  this  part  of  the  ner- 
vous system. 

Other  interesting  observations  which  deal  with  the  action 
of  this  principle  upon  the  metabolism  of  the  body  or  with  the 
pathological  changes  induced  by  toxic  doses  cannot  be  taken 
up  here. 

The  discovery  of  the  chemical  structure  and  pharmacological 
properties  of  epinephrin  has  greatly  encouraged  investigators 


36  JOHN   J.    ABEL 

to  take  up  the  isolation  of  other  active  principles.  Thus  Abelous32 
and  his  co-workers  showed  that  the  intravenous  injection  of 
extracts  from  putrid  meat  caused  a  rise  of  an  animal's  blood 
pressure.  Barger  and  Walpole33  then  proved  that  this  effect 
was  due  to  the  presence  of  isoamylamine,  phenylethylamine 
and  parahydroxyphenylethylamine. 

These  amines  are  produced  by  putrefactive  bacteria  from  pro- 
teids,  and  they  exhibit  pressor  or  blood  pressure  raising  effects 
that  in  general  are  very  similar  to  those  produced  by  epinephrin. 
A  close  similarity  in  chemical  structure  of  two  of  these  amines, 
phenylethylamine  and  parahydroxyphenylethylamine,  to  epine- 
phrin is  shown  in  the  graphic  chemical  formulae  which  will  pres- 
ently be  given.  The  last  named  base  is  of  special  interest  to 
us  since  Barger  has  discovered  that  it  is  also  present  in  ergot 
and  is  in  some  degree  responsible  for  the  characteristic  activities 
of  this  drug.  It  is  also  present  to  a  small  extent  in  Emmenthaler 
cheese.  More  remarkable  still  is  the  discovery  of  Henze  that 
this  amine  is  the  effective  principle  of  a  highly  active  poison 
produced  by  the .  posterior,  so-called,  salivary  glands  of  a  cer- 
tain cephalapod  found  in  the  Bay  of  Naples.  It  has  long  been 
known  that  this  mollusc  renders  its  prey,  as  the  crab,  quickly 
helpless  by  means  of  this  poison  and  until  Henze's  discovery  it 
was  believed  to  be  a  toxalbumin. 

We  find,  therefore,  that  p-hydroxyethylamine  is  produced  by 
putrefactive  bacteria,  that  it  is  present  in  ergot  (the  permanent 
mycelium  of  the  fungus,  claviceps  purpurea)  and  that  it  is  the 
product  of  the  metabolism  of  a  glandular  tissue.  In  each  case 
it  may  be  assumed  that  it  is  obtained  by  chemical  reactions  from 
the  protein  molecule,  its  immediate  precursor  being  the  innocuous 
tyrosine. 

By  merely  splitting  off  a  molecule  of  CO2  from  tyrosin,  as  was 
demonstrated  by  Barger,  we  at  once  secure  this  amine,  as  shown 
by  the  accompanying  formulae.  As  a  recent  writer  has  remarked, 
"Our  poisons  and  our  drugs  are  in  many  instances  the  close  rela- 

32Compt.  rend.  Soc.  de  Biol.  vol.  58,  I,  pp.  463  and  530,  (1906);  vol.  64,  p. 
907,  1908. 

33  Jour,  of  Physiol.,  vol.  38,  p.  343,  1909. 


EXPERIMENTAL   AND    CHEMICAL   STUDIES   OF   THE   BLOOD      37 

tives  of  harmful  compounds  that  represent  the  intermediary 
steps  in  the  daily  routine  of  metabolism."34 

The  fact  that  putrefactive  micro-organisms  .can  produce 
poisonous  amines  by  decarboxylating  the  harmless  amino  acids 
has  become  of  the  highest  importance  to  medicine.  It  would 
appear  that  we  have  at  last  got  onto  the  right  road  for  the  chem- 
ical investigation  of  alimentary  toxaemia  and  its  alleged  conse- 
quences, such  as  arteriosclerosis  and  chronic  renal  disease. 
Phenylalanine,  tyrosine,  tryptophane  and  histidine,  the  harm- 
less precursors  of  toxic  amines,  are  always  present  in  the  intestine 
and  when  they  are  acted  upon  by  an  excessive  number  of  certain 
micro-organisms,  the  resulting  toxic  bases  will  surely  be  formed 
in  excess.  If  they  are  then  taken  up  into  the  blood  in  quantities 
too  large  for  transformation  by  the  liver,  or  other  defensive 
organs,  into  less  harmful  derivatives  they  must  inevitably  mani- 
fest their  pharmacological  and  toxicological  properties.  Let 
me  give  one  further  example  of  recent  advances  in  this  field. 
It  has  been  shown  by  Barger  and  Dale35  that  the  highly  poisonous 
depressor  base,  /5-imino-azolylethylamine  may  be  isolated  from 
the  intestinal  mucosa,  and  Berthelot  and  Bertrand36  have  demon- 
strated that  it  is  in  all  probability  formed  in  the  intestinal  canal 
from  histidine  by  the  decarboxylating  action  of  a  bacillus  newly 
discovered  by  them  which  they  have  named  Bacillus  aminophilus 
intestinalis.  .These  investigators  have  shown  that  their  bacillus 
produces  the  base  from  histidine  even  in  the  presence  of  0.3 
per  cent  lactic  acid,  unless,  indeed,  an  excess  of  glucose  be  pres- 
ent, in  which  case  only  this  is  attacked,  and  they  have  also  made 
the  interesting  observation  that  rats,  fed  on  a  milk  diet,  are 
not  affected  by  either  Proteus  vulgaris  or  Bacillus  aminophilus 

34  Jour.  Amer.  Med.  Assoc.,  editorial  comment,  vol.  62,  Jan.  3,  1914. 

35  Jour,  of  Physiol.,  vol.  40,  p.  1910,  vol.  41,  p.  499,  1910-1911.    Consult  also 
the  work  of  Ackermann  who  first  demonstrated  that  when  pure  histidine  is  sub- 
mitted to  the  action  of  putrefactive  bacteria  a  considerable  yield  of  /3-imino- 
azolylethylamine  is  produced.     Ztschr.  f.  physiol.  Chem.,  vol.  64,  p.  504,  1910. 

36  Compt.  rend.  de.  1'Acad.  des  Sciences,  vol.  154,  pp.  1643  and  1826.     See  also 
Mellenby  and  Twort:  On  the  presence  of  /3-imino-azolylethylamine  in  the  in- 
testinal wall,  with  a  method  of  isolating  a  bacillus  from  the  alimentary  canal 
which  converts  histidine  into  this  substance,  Jour,  of  Physiol.,  45,  p.  53. 


38  JOHN   J.    ABEL 

intestinalis  when  these  organisms  are  given  separately,  but  that 
when  they  are  given  simultaneously  the  rats  succumb  to  a  diar- 
rhoea in  from  4  to  8  days. 

Investigations  on  the  pharmcological  behavior  of  /3-imino- 
azolylethylamine  have  shown  that  it  acts  very  powerfully  on 
plain  muscle,  stimulating  the .  isolated  uterus,  for  example,  to 
contraction  in  the  almost  unbelievable  dilution  of  1 :250,000,000.37 
The  muscular  coats  of  the  guinea  pig's  bronchioles  are  so  sensi- 
tive to  its  action  that  large  pigs  are  killed  in  a  few  minutes  by 
the  intravenous  injection  of  a  half  a  milligram.  The  death  of 
the  animal  is  due  to  asphyxia  produced  by  a  spasm  of  the  bron- 
chioles. Recently  investigators  have  been  much  occupied  in 
studying  similar  features  in  the  symptoms  of  the  poisoning  by 
large  doses  of  the  base  and  those  observed  in  anaphylactic  shock 
(action  on  the  circulation,  body  temperature,  respiration,  etc.), 
and  some  do  not  hesitate  to  affirm  that  the  poisons  of  anaphylac- 
tic shock  must  be  put  into  the  same  pharmacological  class  with 
the  proteinogenous  bases  that  we  have  been  considering. 

We  may  now  give  the  cherriical  formulae  that  illustrate  the 
various  relationships  that  have  been  discussed. 

OH 


1 .  Epinephrin,  adrenaline,  suprarenin,  pos- 


sibly derived  by  decarboxylation  from  a 
OH  •  OH  •  CH2NH  •  CH3    still  unknown  amino  acid,  dioxyphenyl- 

a-methylamino-j8-oxypropionic  acid,  as 
suggested  by  M.  Guggenheim,  Therap. 
Monatsh.,  xxvii,  p.  508,  1913 

OH 


CH  .  OH  .  CH  .  NH  .  CH3         CH  -  OH  -  CH2NH  .  CH3 

Epinephrin 
OOH 
(Unknown  amino-acid) 


C 


37  See  Frohlich  and  Pick:  Arch.  f.  exp.  Pathol.  u.  Pharraakol.,  vol.  71,  p.  23, 
and  Sugimoto:  Ibid.,  vol.  74,  p.  27. 


EXPERIMENTAL   AND    CHEMICAL   STUDIES    OF   THE  'BLOOD      39 
OH 


2.     |       |  p-Hydroxyphenylethylamine,  derived  from 

\/  p-hydroxyphenyl-a-amino-propionic    acid,    or 

CH2  •  CH2  •  NH2  tyrosine,  as  follows : 

OH  OH 

-t  I     I         +       co2 

H2  -  CH .  NH2  •  COOH  CH2 .  CH2 .  NH2 

Tyrosine  p  -Hydroxyphenylethylamine 

(Tyramine) 


3.     |       |  Phenylethylamine,  derived   by   decarboxylation 

from  phenyl-a-amino-propionic  acid  or  phenyl- 
CH2  •  CH2NH2     alanine,  as  follows: 

/\ 

+     C02 

CH2-  CH.  NH2  COOH          CH2 .  CH2  NH2 
Phenylalanine 


CH 

/     \ 

4.     HN        N  jS-Imidoazolylethylamine,  histamin, 

obtained  by  decarboxylation  of  his- 
C  -  CH2  •  CH2  •  NH2    tidine,  as  follows  : 


CH  CH 

/     \  /     \ 

HN       N  -  >        HN       N          +          CO2 

I  I  I 

HC=C  .  CH2  •  CH  •  NH2  -  COOH       HC=C  -  CH2  .  CH  .  NH2 

IV.  I  come  now  to  the  concluding  portion  of  my  address.  That 
science  in  general  is  a  basic  fact  in  the  development  of  com- 
merce and  industry  seems  to  be  fully  appreciated  in  this  city 
as  shown  by  the  establishment  of  the  Mellon  Institute  of  Indus- 
trial Research  and  School  of  Specific  Industries,  through  the 
munificence  of  two  of  your  public  spirited  citizens,  the  Messrs. 
Richard  B.  and  Andrew  W.  Mellon.  I  believe  that  no  act  of 
their  lives  will  give  them  more  enduring  satisfaction  than  this 
which  marks  out  your  city  as  one  more  great  center  of  industry 


40  JOHN   J.    ABEL 

which  acknowledges  the  dependence  of  all  advance  in  material 
civilization  upon  the  quiet  labors  of  the  investigator.  This  de- 
pendence has  been  forcibly  expressed  by  former  ambassador 
James  Bryce  in  an  address  to  the  members  of  the  National  Acad- 
emy of  Sciences. 

You  men  of  science  are  really  the  rulers  of  the  world.  It  is  in  your 
hands  that  lies  control  of  the  forces  of  activity;  it  is  you  who  are  going 
to  make  the  history  of  the  future  because  all  commerce  and  all  industry 
is  today  far  more  than  ever  the  child  and  product  of  science.  .  .  . 
It  is  in  your  hands  that  the  future  lies,  far  more  than  in  those  of  military 
men  or  politicians. 

Let  me  also  in  this  connection  recall  the  inspiring  words  of 
that  great  investigator  and  benefactor  of  mankind,  Louis  Pas- 
teur, which  point  out  the  still  wider  influence  of  science: 

"Laboratories  and  discoveries  are  correlative  terms/'  he  wrote; 
"if  you  suppress  laboratories,  physical  science  will  be  stricken  with 
barrenness  and  death,  it  will  become  mere  powerless  information 
instead  of  a  science  of  progress  and  futurity;  give  it  back  its  laboratories 
and  life,  fecundity  and  power  will  reappear.  .  .  Ask  that  they  be 
multiplied  and  completed.  They  are  the  temples  of  the  future,  of 
riches  and  of  comfort.  There  humanity  grows  greater,  better,  stronger. 
There  she  can  read  the  works  of  Nature,  works  of  progress  and  universal 
harmony,  while  humanity's  own  works  are  too  often  those  of  barbarism, 
of  fanaticism  and  destruction." 

And  here  I  shall  permit  myself  to  speak  more  specifically  of 
the  paramount  importance  of  chemistry  in  biological  and  medical 
research.  The  subjects  to  which  I  have  been  calling  your  atten- 
tion tonight,  viz.,  the  still  unknown  chemical  properties  and 
molecular  structure,  with  the  single  exception  of  epinephrin,  of 
the  mysterious,  correlating  substances  stored  and  formed  in  the 
many  organs  of  internal  secretion,  and  the  equally  unknown 
character  of  numerous  constituents  of  the  circulating  blood, 
both  offer  a  virgin  field  to  the  biologist  with  a  chemist's  training. 

The  practical  importance  of  decisive  chemical  advances 
along  this  line  is  hardly  to  be  over-stated.  At  present  we 
meet  only  vast  confusion  and  contradictory  theories.  A  single 


EXPERIMENTAL   AND    CHEMICAL   STUDIES    OF    THE   BLOOD      41 

clean-cut  discovery,  the  separation  from  another  of  these  glands 
of  a  definite  chemical  individual  shown  to  possess  one  or  more 
of  the  specific  actions  of  the  gland  would  clear  way  the  mists 
at  once,  and  we  should  see  the  same  rapid  progress  that  has 
followed  the  isolation  of  epinephrin,  which  is  only  one,  and 
perhaps  not  the  most  important  constituent  of  the  suprarenal 
gland. 

What  a  flood  of  light  was  thrown  on  the  whole  question  of 
carbohydrate  metabolism  in  the  discovery  by  Claude  Bernard 
of  glycogen  in  the  liver!  Innumerable  fruitful  researches  have 
come  from  this  as  a  starting  point,  and  their  bearing  on  our 
understanding  of  such  diseases  as  diabetes  mellitus  has  been  of 
the  most  fundamental  nature. 

Miescher's  discovery  of  the  existence  of  protamin  nucleate 
in  the  spermatozoan  heads  of  the  Rhine  salmon  is  another  case 
of  the  far-reaching  importance  of  a  definite  chemical  fact  for 
both  biology  and  medicine.  For  further  discoveries  in  the 
field  of  nucleinic  acids,  a  later  worker,  Professor  Kossel,  received 
the  Nobel  prize.  To  name  only  one  practical  outcome  of  these 
discoveries,  our  theories  of  the  origin  of  uric  acid  in  gout  and 
of  the  purins  in  general  have  undergone  entire  transformation. 

The  actual  finding  of  definite  and  specific  chemical  principles 
in  the  organs  of  internal  secretion  has  in  each  case  an  importance 
in  the  way  of  explaining  and  correlating  a  large  number  of  dis- 
connected facts,  only  to  be  likened  to  the  discovery  of  the  etiologi- 
cal  cause  of  an  infectious  disease.  The  bacillus  of  tuberculosis 
or  of  typhoid,  or  the  protozoa  of  syphilis  and  sleeping  sickness, 
are  illuminating  examples  in  point.  Here,  too,  simplicity  at 
once  took  the  place  of  what  had  been  confused  and  complex, 
and  a  multitude  of  already  recorded  facts  fell  into  their  proper 
place. 

From  my  insistence  on  our  ignorance  of  the  specific  secretory 
products  of  the  organs  of  internal  secretion,  and  of  numerous 
constituents  of . the  blood,  it  is  not  to  be  inferred  that  important 
chemical  facts  are  lacking  with  regard  to  these  tissues.  On 
the  contrary,  a  vast  number  of  facts,  some  of  immediate,  others  of 
potential  significance,  have  been  amassed  by  an  army  of  workers 


42  JOHN   J.    ABEL 

in  the  past  30  years;  it  is  their  relation  to  each  other  and  to  an 
underlying  cause  that  remains  obscure.  For  example:  it  has  been 
recently  shown  by  Cramer  and  Krause38  that  when  fresh  thyroids 
are  fed  to  cats  or  rats  kept  on  a  carbohydrate-rich  diet,  the 
glycogenic  function  of  the  liver  is  inhibited,  and  in  consequence 
this  organ  is  soon  found  to  contain  only  traces  of  glycogen. 
And  these  investigators  suspect  that  the  well  known  action  of 
thyroid  secretion  on  the  metabolism  is  effected  through  this 
change  in  the  carbohydrate  metabolism.  But  this  important 
discovery  cannot  reach  its  full  significance  until  we  know  the 
chemical  properties  of  the  special  hormone  of  the  thyroid  gland 
which  is  carried  in  the  blood  to  the  liver  and  there  prevents  the 
formation  of  glycogen  even  though  the  food  may  contain  an 
abundance  of  carbohydrate. 

Thus,  too,  one  of  the  facts  known  about  the  parathyroids, 
as  shown  by  MacCallum  and  Voegtlin,39  is  that  their  removal 
from  the  body  is  followed  by  increased  excretion  of  calcium  salts. 
This  chemical  discovery  also  cannot  yet  be  brought  into  a  causal 
connection  with  a  definite  chemical  constituent  of  the  gland. 

That  I  may  not  be  accused  of  placing  too  much  emphasis 
upon  only  one  mode  of  attack  in  biological  and  medical  research, 
let  me  say  that  I  am  fully  aware  of  how  many  sided  are  all  these 
problems  and  that  fundamental  discoveries  have  been  made 
and  will  continue  to  be  made  without  the  aid  of  chemistry. 
This  is  true  especially  in  the  field  of  morphology.  But  as  soon 
as  we  touch  the  complex  processes  that  go  on  in  a  living  thing, 
be  it  plant  or  animal,  we  are  at  once  forced  to  use  the  methods 
of  this  science.  No  longer  will  the  microscope,  the  kymograph, 
the  scalpel  avail  for  the  complete  solution  of  the  problem.  For 
the  further  analysis  of  these  phenomena  which  are  in  flux  and 
flow,  the  investigator  must  associate  himself  with  those  who  have 
labored  in  fields  where  molecules  and  atoms  rather  than  multi- 
cellular  tissues  or  even  unicellular  organisms  are  the  units  of  study. 
Today  investigators  in  biology  and  medicine  are  reaching  out  with 
eager  hands  into  the  more  exact  branches  of  science.  The  great 

38  Proc.  Roy.  Soc.  B.,  vol.  86,  p.  550,  1913. 

39  Jour.  Exp.  Med.,  vol.  ii,  p.  118,  1909. 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   43 

progress  in  biology  and  in  medicine  that  has  been  made  during 
the  past  century  proves  that  advantages  hardly  to  be  imagined 
must  follow  upon  the  further  application  of  physics  and  chemistry 
to  these  sciences.  A  striking  example  of  the  debt  which  medi- 
cine owes  to  that  newer  branch  of  chemistry  called  physical 
chemistry  is  seen  in  our  better  understanding  in  the  last  twenty 
years  of  certain  dynamic  equilibria  of  the  body,  such  as  the 
relationship  between  the  hydrogen  and  the  hydroxyl  ions  of  the 
blood  and  tissues,  of  surface  tension,  osmotic  pressure  and  the 
colloidal  state. 

I  also  recognize  that  all  the  various  aspects  of  any  one  problem 
in  our  field  are  intimately  bound  together,  and  that  progress 
along  the  chemical  side,  for  instance,  of  a  question  may  have 
to  wait  on  the  clearing  up  of  the  morphological  side.  When  I 
have  the  honor  of  being  consulted  by  a  young  man  who  has 
not  yet  found  himself  intellectually  but  who  is  filled  with  the 
desire  to  devote  his  life  to  some  branch  of  medicine,  be  it  clinical 
medicine,  pathology,  hygiene,  bacteriology,  physiology  or  phar- 
macology, my  advice  always  is,  "Study  chemistry  for  at  least 
three  years.  Try  with  all  your  power  to  master  enough  of  this 
great  science  to  start  you  in  your  career."  Why  not  make 
this  attempt  at  a  time  of  life  when  one  still  takes  kindly  to  a 
rigid  discipline40  such  as  this  science  exacts?  To  this  prepara- 
tion must  be  added  the  special  medical  training  of  another 
four  or  more  years.  A  long  road  to  travel?  But  I  find  that  many 
young  men  have  entered  upon  it  with  great  enthusiasm. 

I  do  not  mean  that  this  long  tutelage  is  to  be  a  cramming  pro- 
cess. I  have  in  mind  conditions  where  these  students  will 
be  constantly  under  the  influence  of  teachers  who  are  themselves 
investigators  and  daily  engaged  in  the  search  for  new  truths. 
Under  the  stimulus  of  such  examples  our  young  man  is  saved 

40  The  professor  of  physics  in  McGill  University,  Dr.  A.  S.  Eve,  has  recently 
expressed  himself  as  follows  in  a  paper  describing  modern  discoveries  on  the 
constitution  of  the  atom  (Jour.  Franklin  Institute,  1915,  p.  269):  "It  may  be 
noted  that  the  discoveries  set  forth  in  this  brief  summary  have  been  achieved 
by  savants  in  the  western  half  of  Europe,  and  it  may  be  asked  if  the  education 
in  the  New  World  is  at  the  present  time  sufficiently  thorough,  imaginative  and 
philosophical." 


44  JOHN   J.    ABEL 

from  the  sterile  life  of  the  mere  crammer,  because  he  sees  the 
relation  of  what  he  learns  to  living  questions.  During  this 
period  of  study  and  growth  he  will  himself  make  occasional  at- 
tempts at  the  solution  of  problems.  Even  with  the  best  prepara- 
tion, workers  in  our  fields  have  always  to  return  again  and  again 
to  the  fundamental  sciences  for  assistance. 

But  to  what  end  is  all  this  preparation  for  our  young  man? 
Is  it  solely  that  he  may  solve  problems  whose  solution  is  of 
practical  value  to  mankind?  Is  his  mind  to  shape  itself  only  to 
the  insistent  demands  of  utility?  Even  then  our  method  of 
training  will  yield  the  largest  profit.  But  it  does  vastly  more 
than  that.  Thus  trained  our  young  scholar  will  be  able  to  see 
beyond  the  immediately  practical  problem,  even  though  it  be 
as  great  a  thing  as  the  discovery  of  the  cause  and  cure  of  the 
plague  that  decimates  a  people.  Greater  even  than  the  greatest 
discovery  is  it  to  keep  open  the  way  to  future  discoveries.  This 
can  only  be  done  when  the  investigator  freely  dares,  moved  as  by 
an  inner  propulsion,  to  attack  problems  not  because  they  give 
promise  of  immediate  value  to  the  human  race,  but  because 
they  make  an  irresistible  appeal  by  reason  of  an  inner  beauty. 
Some  of  the  greatest  investigators  indeed  have  been  fascinated  by 
problems  of  immediate  utility  as  well  as  by  those  that  deal  with 
abstract  conceptions  only.  Helmholtz  invented  the  ophthalmos- 
scope  and  thus  made  modern  ophthalmology  possible,  and  at 
the  same  time  did  work  of  the  highest  order  in  theoretical  physics 
and  wrote  on  the  nature  •  of  the  mathematical  axioms  and  the 
principles  of  psychology.  Lord  Kelvin  took  out  patents  on 
great  improvements  in  the  compass  and  on  oversea  telegraphy 
and  also  made  contributions  to  our  knowledge  of  the  ultimate 
constitution  of  the  atom  and  the  properties  of  the  ether.  From 
this  point  of  view  the  investigator  is  a  man  whose  inner  life 
is  free  in  the  best  sense  of  the  word.  In  short,  there  should  be 
in  research  work  a  cultural  character,  an  artistic  quality,  elements 
that  give  to  painting,  music  and  poetry  their  high  place  in  the  life 
of  man. 

Ladies  and  gentlemen,  I  have  attempted  in  this  hour  to  point 
out  some  recent  advances  that  have  been  made  in  the  study  of 


EXPERIMENTAL  AND  CHEMICAL  STUDIES  OF  THE  BLOOD   45 

the  blood  and  of  the  organs  of  internal  secretion,  and  have  cited 
the  beneficent  effects  of  even  these  small  advances — a  very  few 
bright  stars  in  a  darkened  sky — in  order  to  emphasize  the  great 
r61e  that  chemistry  is  destined  to  play  in  biology  and  medicine. 
I  have  strongly  urged  that  those  who  are  to  be  medical  teachers 
and  investigators  should  not  content  themselves  with  a  mere 
smattering,  but  endeavor  to  acquire  a  really  sound  training  in 
one  of  the  fundamental  sciences. 

You,  my  colleages,  working  with  open-minded  and  generous 
trustees,  must  see  to  it  that  the  men  selected  for  important 
posts  shall  be  those  that  are  capable  of  training  and  inspiring 
the  young  men  who  in  their  turn  will  furnish  the  leadership  of 
the  future. 

In  our  country  many  agencies  combine  to  foster  the  higher 
learning.  It  is  to  the  lasting  honor  of  men  of  wealth  that  they 
have  appreciated  the  need  for  institutes  of  research  and  in  a 
number  of  notable  instances  have  placed  large  sums  at  the 
disposal  of  science.  They  have  responded  nobly  to  that  appeal 
of  Pasteur  which  I  have  already  cited  in  which  he  calls  labora- 
tories "the  temples  of  the  future,  of  riches  and  of  comfort." 


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